Tuberculosis risk in patients with Crohn's disease on biologics: a retrospective analysis of the Japanese Medical Claims Database.

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.

Effects on anorectal function of endoscopic submucosal dissection for rectal tumors involving the dentate line.

OBJECTIVE: Endoscopic submucosal dissection (ESD) is a specific procedure that uses an electrosurgical knife for en-bloc resectioning large tumors. However, no study has examined the effect of ESD on the defecation function of patients with rectal tumors. We aimed to investigate the potential effects caused by ESD by analyzing changes in the morphology and movement of the anorectum pre- and post-ESD. METHODS: This prospective observational study included 11 patients with anorectal tumors who underwent ESD between April 2020 and February 2022. Pre-ESD assessments included anorectal manometry and defecography. Post-ESD assessments were conducted 2 months later, including anorectal manometry, defecography, and proctoscopy for ulcer and stenosis evaluation. RESULTS: The median patient age was 73 years, including seven males and four females. Eight patients (73%) had a tumor in the lower rectum, and the extent of resection was less than 50% of the rectal lumen. Resection reached the dentate line in six cases (55%). In the patients with post-ESD mucosal defects involving the dentate line, the median of functional anal canal length significantly decreased from (3.4 cm pre-ESD to 2.8 cm post-ESD, p = 0.04). Defecography revealed one case with incomplete evacuation (<50%) and incontinence post-ESD. Interestingly, patients with pre-existing rectoceles noted resolution of lesions post-ESD. None of the patients reported daily constipation or fecal incontinence. CONCLUSIONS: While rectal ESD is unlikely to cause significant real-world defecation difficulties, alterations in rectal and anal canal morphology and function may occur if the dentate line is involved in the resection range.

Efficacy evaluation of upper gastrointestinal endoscopy screening for secondary prevention of gastric cancer using the standardized detection ratio during a medical check-up in Japan.

We used standardized detection ratio to evaluate the quality of nasal upper gastrointestinal endoscopy screening for the secondary prevention of gastric cancer, and examined the gastric cancer risk in the era of total Helicobacter pylori (H. pylori) eradication. We performed 21,931 upper gastrointestinal endoscopies, 77 subjects were diagnosed with gastric cancer. Of these, 28 had gastric cancer after H. pylori eradication, 47 had gastric cancer with H. pylori-positive or others, and 2 had H. pylori-negative gastric cancer. The Standardized detection ratios for men and women were 5.33 and 4.82, respectively. Multivariable logistic regression analyses performed exclusively on first endoscopy subjects, excluding H. pylori-negative gastric cancer, revealed that smoking was a risk factor for developing gastric cancer (adjusted odds ratio, 3.31; 95% confidence interval, 1.65-6.64; p = 0.001). A statistically significant interaction was found between daily alcohol consumpption and H. pylori eradication on gastric cancer development (p = 0.005). In conclusion, relatively high standardized detection ratio values suggest that an appropriate endoscopic diagnosis of gastric cancer should be performed during a medical check-up. Smoking is a risk factor for developing gastric cancer, and continued alcohol consumption suggests a possible risk for developing gastric cancer after H. pylori eradication.

Epidemiology and Risk Factors of Eosinophilic Esophagitis in Japan: A Population-Based Study.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) has been increasingly diagnosed globally. However, there have been few general population-based studies in Asia. The aim of this study was to investigate EoE epidemiology in the Japanese general population. METHODS: We analyzed an employer-based health insurance claim database from January 2005 to September 2022. EoE cases were identified on the basis of the International Statistical Classification of Diseases and Health-related Problems, 10th Revision code, K20.0. We calculated the incidence and prevalence of EoE using Poisson regression and binomial distribution, respectively. Using 10 matched controls for each EoE case, a nested case-control study was performed to identify potential risk factors for EoE. RESULTS: Of 15,200,895 individuals, 1010 EoE cases were identified. The incidence and prevalence of EoE were 2.82 (95% confidence interval [CI], 2.44-3.26) per 100,000 person-years and 10.68 (95% CI, 10.01-11.37) per 100,000 people in 2022, nearly 3 and 8 times as high as those in 2017, respectively. Smoking was associated with decreased risk of EoE (odds ratio [OR], 0.45, 0.36-0.56, P < .001), whereas alcohol consumption (OR, 1.51, 1.21-1.88, P < .001) was associated with increased risk of EoE along with several allergic conditions and psychiatric disorders. EoE was not related to either body mass index or lifestyle-related diseases such as hypertension, diabetes mellitus, hyperuricemia, and dyslipidemia. CONCLUSIONS: The incidence and prevalence of EoE in Japan have steadily increased over the past 2 decades. Nevertheless, EoE remains less common in Japan compared with the United States and Western Europe. Factors contributing to the epidemiology of EoE on a global basis may improve our understanding of the contribution of genetic and environmental risk factors.

Neutrophil extracellular trap formation and its implications in nonsteroidal anti-inflammatory drug-induced small intestinal injury.

BACKGROUND AND AIM: Nonsteroidal anti-inflammatory drugs (NSAIDs) damage the small intestine via neutrophil infiltration driven by the mucosal invasion of enterobacteria. The antimicrobial function of neutrophils is partially dependent on neutrophil extracellular traps (NETs). Excessive NET formation has been associated with several inflammatory diseases. Here, we aimed to investigate the role of NETs in NSAID-induced small intestinal damage using human samples and an experimental mouse model. METHODS: Human small intestine specimens were obtained from NSAID users during double-balloon enteroscopy. Wild-type, protein arginine deiminase 4 (PAD4) knockout, and antibiotic-treated mice were administered indomethacin to induce small intestinal injury. The expression of NET-associated proteins, including PAD4, citrullinated histone H3 (CitH3), cell-free DNA, and myeloperoxidase (MPO), was evaluated. RESULTS: The double-positive stained area with CitH3 and MPO, which is specific for neutrophil-derived extracellular traps, was significantly high in the injured small intestinal mucosa of NSAID users. In a mouse model, small intestinal damage developed at 6 h after indomethacin administration, accompanied by increased mRNA levels of interleukin-1ß and keratinocyte chemoattractant and elevated NET-associated protein levels of PAD4, CitH3, and MPO in small intestine and serum levels of cell-free DNA. Both genetic deletion and pharmacological inhibition of PAD4 attenuated this damage by reducing the mRNA expression of inflammatory cytokines and NET-associated proteins. Furthermore, mice pretreated with antibiotics showed resistance to indomethacin-induced small intestinal damage, with less NET formation. CONCLUSION: These results suggest that NETs aggravate NSAID-induced small intestinal injury. Therefore, NET inhibition could be a potential treatment for NSAID-induced small intestinal injury.

Correlation between anxiety and decreased quality of life in patients with non-esophageal eosinophilic gastrointestinal diseases.

Background and Aim: Mental status such as anxiety and depression in patients with non-esophageal eosinophilic gastrointestinal diseases (non-EoE EGIDs) has not been studied. The aim of this study was to evaluate whether patients with non-EoE EGIDs had mental disorders and decreased mental-health-related quality of life (QOL) similar to those in patients with disorders of gut-brain interaction (DGBI). Methods: We enrolled patients with non-EoE EGIDs and DGBI visiting the Osaka Metropolitan University Hospital, and the measures listed below were compared between the groups. We collected data using the following questionnaires: hospital anxiety and depression scale, and short form (SF)-8 including mental component summary (MCS)-8. Results: We evaluated 21 and 17 patients with non-EoE EGIDs and DGBI, respectively. The anxiety score was not significantly different between the groups. The proportion of patients with possible anxiety was not significantly different between the groups (19.0% vs 33.3%). These results show that patients with non-EoE EGIDs had anxiety that might be equivalent to that of patients with DGBI. The depression score and proportion of patients with possible depression in the non-EoE EGID group tended to be lower than those in the DGBI group. MCS-8 scores were not significantly different between the non-EoE EGID and DGBI groups, which might imply an equivalent decrease in mental-health-related QOL in both groups of patients. In patients with non-EoE EGIDs, the anxiety score had a significant inverse association with the MCS-8 score. Conclusions: Patients with non-EoE EGIDs may have anxiety that correlates with decreased mental-health-related QOL.

Responses of Proton Pump Inhibitors and Potassium-Competitive Acid Blockers According to Outcomes of Symptom, Endoscopy, and Histology in Patients With Eosinophilic Esophagitis.

GOALS: We aimed to examine the response rate to proton pump inhibitors (PPIs) and potassium-competitive acid blockers and the prevalence of topical corticosteroid (TCS) therapy as the second-line treatment for eosinophilic esophagitis (EoE). BACKGROUND: Acid-suppressive drugs such as PPIs and potassium-competitive acid blockers are often used to treat EoE. Treatment response is based on outcomes including symptoms, endoscopy, and histology; however, the detailed response rate to PPI/P-CAB is unknown. STUDY: In total, 236 patients with histologically confirmed EoE who received PPI/P-CAB as the first-line treatment were included. We assessed the symptoms, endoscopic reference score (EREFS), and histology [eosinophils per high-power field (eos/hpf)] 8 weeks after PPI/P-CAB administration. Complete normalization was defined as the disappearance of symptoms, EREFS score 0, or 0-1 eos/hpf, and response as disappearance or improvement of symptoms, EREFS score ≤2, or <15 eos/hpf. The prevalence of TCS therapy in each response group was assessed. RESULTS: Complete normalization was achieved in 25%, 50%, 36%, and 8% of patients for symptoms, endoscopy, histology, and all 3 outcomes, respectively. The response rates were 81%, 87%, 87%, 75%, and 60% for symptoms, endoscopy, histology, and all 3 outcomes, respectively. TCS use was significantly lower (8%) in patients who achieved response of all 3 outcomes than in other groups and was dependent on the number of outcomes with nonresponse. CONCLUSIONS: Complete normalization of symptoms, endoscopy, and histology using PPI/P-CAB is uncommon. Based on treatment efficacy by response/nonresponse, TCS was the secondary treatment in cases with an increase in the number of nonresponse outcomes.

Superficial oesophageal mucosal innervation may contribute to severity of symptoms in oesophageal motility disorders.

BACKGROUND: Mechanisms underlying perception of dysphagia and chest pain have not been completely elucidated, although oesophageal mucosal afferent nerves might play an important role. AIMS: To evaluate the relationship between oesophageal mucosal afferent nerves and the severity of dysphagia and chest pain in oesophageal motility disorders. METHODS: We prospectively recruited patients with oesophageal motility disorders having dysphagia and/or chest pain from whom oesophageal biopsies were obtained. High-resolution manometry classified patients into disorders of oesophagogastric junction (OGJ) outflow and disorders of peristalsis. Symptom severity was assessed using validated questionnaires including Brief Oesophageal Dysphagia Questionnaire (BEDQ). Immunohistochemistry was performed on oesophageal biopsies to evaluate the location of calcitonin gene-related peptide (CGRP)-immunoreactive mucosal afferent nerves. Findings were compared to existing data from 10 asymptomatic healthy volunteers. RESULTS: Of 79 patients, 61 patients had disorders of OGJ outflow and 18 had disorders of peristalsis. CGRP-immunoreactive mucosal nerves were more superficially located in the mucosa of patients with oesophageal motility disorders compared to healthy volunteers. Within disorders of OGJ outflow, the location of CGRP-immunoreactive nerves negatively correlated with BEDQ score both in the proximal (ρ = -0.567, p < 0.001) and distal oesophagus (ρ = -0.396, p = 0.003). In the proximal oesophagus, strong chest pain was associated with more superficially located mucosal nerves than weak chest pain (p = 0.04). Multivariate analysis showed superficial nerves in the proximal oesophagus was independently associated with severe dysphagia in disorders of OGJ outflow (p = 0.008). CONCLUSIONS: Superficial location of mucosal nerves in the proximal oesophagus might contribute to symptoms, especially severe dysphagia, in disorders of OGJ outflow.

The impact of COVID-19 on Japanese patients with eosinophilic gastrointestinal disorders during the vaccination era.

Background: Eosinophilic gastrointestinal disorders (EGIDs) are chronic allergic diseases categorized as eosinophilic esophagitis (EoE) and non-EoE EGIDs. Few studies regarding the association between EGIDs and coronavirus disease 2019 (COVID-19) have been reported. Although most Japanese individuals received the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine, the incidence of COVID-19 remained high in 2022. This study examines the incidence of COVID-19 in patients with EGIDs during the vaccination era. Methods: Patients with EGIDs who visited our department between October and December 2022 were enrolled in the study. The incidence and severity of COVID-19 prior to October 1, 2022 were determined. Patients who reported having COVID-19 also reported their hospitalization history, intensive care unit admissions, and EGID flares. The number of SARS-CoV-2 vaccinations received and treatment for EGIDs were obtained from the patients' medical records. Results: Of 111 patients with EGIDs (65 with EoE and 46 with non-EoE EGIDs) included in this study, 31 (28%) patients reported having COVID-19, including 14 (22%) with EoE and 17 (37%) with non-EoE EGIDs. Fifty-nine (84%) patients received two or more vaccinations, and 11 (16%) patients received no vaccinations. COVID-19 was mild in all but one patient who had moderate symptoms. COVID-19 was not associated with EGID flares. EGID treatments and an unvaccinated status were not associated with an increased risk of COVID-19. Conclusion: COVID-19 was mild in patients with EGIDs and not associated with EGIDs flares during the vaccination era. There was a relatively high incidence of COVID-19 among patients with non-EoE EGIDs.

Impact of the COVID-19 Pandemic on the Lifestyle and Psychosocial Behavior of Patients with Inflammatory Bowel Diseases: A Narrative Review.

The coronavirus disease (COVID-19) pandemic has had a considerable impact on the global healthcare system and potentially the clinical course of patients with inflammatory bowel disease (IBD). Although IBD is a chronic disease, its therapy (except steroid therapy) does not increase the risk of contracting or aggravating COVID-19. However, the clinical course of patients is significantly influenced by environmental factors. Social restrictions due to the pandemic or the fear of contracting the virus have influenced lifestyle and psychosocial behaviors that may worsen the clinical course of patients with IBD. This narrative literature review summarizes the current evidence on the impact of the COVID-19 pandemic on the lifestyle and psychosocial behaviors of patients with IBD. The COVID-19 pandemic negatively affected the lifestyle and psychosocial behaviors of patients with IBD. Furthermore, patients with IBD failed to maintain medication adherence, thus affecting the clinical course of their condition.

Prevalence of elderly eosinophilic esophagitis and their clinical characteristics.

BACKGROUND AND AIMS: Eosinophilic esophagitis (EoE) is predominantly found in middle-aged men among adults. There are few reports about EoE in the elderly, despite an ageing population. The study aimed to define the prevalence and clinical characteristics of EoE amongst older adults. METHODS: Elderly patients (defined as those ≥65 years) were compared to younger adults (18-64) in terms of clinical characteristics (age, gender, presenting symptoms, comorbidities), histological activity (eosinophil count), treatment modality and response to treatment. A pre- existing prospectively generated database of all EoE patients presenting to our department between February 2010 and December 2022 was interrogated. 309 patients who underwent endoscopy and esophageal biopsy and were found to have ≥15 eosinophils/HPF were defined as having EoE and were included for study. Statistical analyses were performed using Fisher's extract test or Mann-Whitney U test. RESULTS: 309 cases of EoE were recorded, mean age 45.7, range (21-88 years), of which20 patients were aged 65 years and over. Compared to younger patients, those aged ≥65 had more medical comorbidities (15 [75%] vs 111[38%], p = 0.002), and instead a non-significant trend toward less fibrosis (0.25 vs 0.46, p = 0.117). Although rate of cases required topical steroid (TCS) therapy was similar, none received repeated or maintenance TCS therapy in elderly. CONCLUSION: In our cohort, only 20 patients (6%) were aged 65 years or older, suggesting that EoE is uncommon in the elderly. The clinical characteristics of EoE in the older age group were similar to the younger patients. Future studies with prospective data collection may determine if EoE disappears with age, or if the younger mean age is reflective of an increasing prevalence in recent years, that may be realized in the elderly EoE population in the future.

Risk factors for adverse events associated with endoscopic submucosal dissection for superficial pharyngeal cancer.

BACKGROUND: Superficial pharyngeal cancer can be treated with curative intent while preserving function using minimally invasive peroral endoscopic resection techniques such as endoscopic submucosal dissection (ESD). However, severe adverse events occasionally occur, such as laryngeal edema requiring temporary tracheotomy and fistula formation. Therefore, we investigated the risk factors for adverse events associated with ESD for superficial pharyngeal cancer. METHODS: This retrospective observational study was conducted at a single institution, and 63 patients who underwent ESD were enrolled. The primary outcome was the risk factors for adverse events associated with ESD. The secondary outcomes were adverse events associated with ESD and their frequency. RESULTS: The overall adverse event rate was 15.9% (10/63). The incidence of laryngeal edema requiring prophylactic temporary tracheotomy was 11.1%, while laryngeal edema requiring emergency temporary tracheotomy, postoperative bleeding, aspiration pneumonia, fistula, abscess, and stricture formation occurred in 1.6% of patients, respectively. Logistic regression analyses showed that a history of radiotherapy for head and neck cancer was a risk factor for adverse events (odds ratio [OR], 16.67; 95% confidence interval [CI], 3.04-91.34; p = 0.001). After adjusting the model for differences in the baseline risk factors using the inverse probability of treatment weighting method, the adverse events were found to increase in association with a history of radiotherapy for head and neck cancer (OR, 39.66; 95% CI,5.85-268.72; p < 0.001). CONCLUSION: History of radiotherapy for head and neck cancer is an independent risk factor for adverse events associated with ESD for superficial pharyngeal cancer. Among adverse events, laryngeal edema requiring prophylactic temporary tracheotomy was particularly high.

Upper gastrointestinal endoscopic findings in functional constipation and irritable bowel syndrome diagnosed using the Rome IV criteria: a cross-sectional survey during a medical check-up in Japan.

BACKGROUND: The Rome IV criteria have been established as an international standard for diagnosing disorders of gut-brain interaction. In this study, we aimed to examine the upper gastrointestinal (GI) endoscopic findings and symptoms of subjects with functional constipation (FC) and irritable bowel syndrome (IBS) of individuals undergoing a medical check-up. METHODS: A total of 13,729 subjects underwent a medical check-up at Osaka City University-affiliated clinic, MedCity21, between April 2018 and March 2019. Among the 5,840 subjects who underwent screening upper GI endoscopy and completed a questionnaire based on the Rome IV criteria, 5,402 subjects were consecutively enrolled after excluding subjects with a large amount of gastric residue (n = 6), those who had previously undergone partial or total gastrectomy (n = 40), or those with daily use of low-dose aspirin (n = 82), nonsteroidal anti-inflammatory drugs (n = 63), or acid secretion inhibitors (n = 308). RESULTS: Robust Poisson regression analyses adjusted for age, sex, Helicobacter pylori infection status, alcohol intake, and smoking habits showed a significant association between FC and corpus erosion (adjusted prevalence ratio [aPR], 2.93; 95% confidence interval [CI], 1.51-5.67; p < 0.01) and red streaks (aPR, 3.83; 95% CI, 2.53-5.79; p < 0.01), whereas IBS was significantly associated with erosive gastritis (aPR, 8.46; 95% CI, 4.89-14.67; p < 0.01) and duodenitis (aPR, 7.28; 95% CI, 3.64-14.59; p < 0.01). Red streaks tended to be associated with IBS (aPR, 1.96; 95% CI, 1.00-3.83; p = 0.05). Subjects with IBS were the most to complain of both upper and lower GI symptoms and psychological symptoms, followed by those with FC and controls. IBS subjects with erosive gastritis or duodenitis had significantly more complaints of stomachache and feeling stressed than those without erosive gastritis or duodenitis (54.5% vs. 18.8%; p = 0.03 and 66.7% vs. 25.0%; p = 0.01). CONCLUSIONS: Subjects with FC and IBS had a variety of upper GI and psychological symptoms. In the upper GI endoscopic findings, corpus erosion and red streaks were associated with FC, and erosive gastritis, duodenitis, and possibly red streaks were associated with IBS.

Pretreatment serum monocyte chemoattractant protein-1 as a predictor of long-term outcome by ustekinumab in patients with Crohn's disease.

BACKGROUND AND AIMS: Ustekinumab has been proven to be effective for treatment of patients with Crohn's disease; however, 30-40% of patients have been reported to lose clinical response within 2 years. We aimed to evaluate the efficacy of ustekinumab and identify predictors of short-term and long-term efficacy in Crohn's disease. METHODS: Patients with Crohn's disease receiving their first ustekinumab infusion in our hospital between June 2017 and September 2020 were prospectively enrolled. Concentrations of serum cytokines and chemokines were measured using a multiplex bead array assay. RESULTS: Fifty-nine Crohn's disease patients were enrolled in this study. Among 34 clinically active patients, 38.2% achieved a clinical response at week 8. None of the assayed factors were associated with short-term clinical response. Cumulative persistence rates of ustekinumab were 77.6% at 1 year and 58.9% at 2 years. Univariate Cox regression analysis revealed that Harvey-Bradshaw Index scores at baseline, concomitant immunomodulator treatment, and concentrations of interferon gamma-induced protein-10, monocyte chemoattractant protein-1 (MCP-1), and interleukin (IL)-1RA, IL-4, IL-6, and IL-8 were significantly associated with loss of efficacy. Multivariate Cox regression analysis found that biologic naïve status (hazard ratio [HR]: 0.1191, 95% confidence interval [CI]: 0.02458-0.5774) and MCP-1 concentrations (HR: 1.038, 95% CI: 1.015-1.062) were significantly and associated with loss of sustained efficacy for ustekinumab treatment. CONCLUSIONS: Our findings suggest that pretreatment serum MCP-1 analysis, combined with a history of biologic use, could be a novel biomarker for predicting the long-term efficacy of ustekinumab in patients with Crohn's disease.

Neutrophil-to-lymphocyte ratio may predict clinical relapse in ulcerative colitis patients with mucosal healing.

Endoscopic mucosal healing (MH) is an important treatment goal for patients with ulcerative colitis (UC). The neutrophil-to-lymphocyte ratio (NLR) reflects systemic inflammation and has been reported to be a useful predictive marker for UC. This study aimed to evaluate the clinical utility of the NLR for predicting clinical relapse in UC patients with MH. We retrospectively enrolled patients with UC who underwent colonoscopy at the Osaka City University Hospital between January 2010 and December 2010, whose Mayo Endoscopic Subscore was 0 or 1. The correlation between the incidence of relapse and demographic factors, including the NLR, was analyzed. We included 129 patients in the present study. The median NLR at the time of endoscopy was 1.98, and differences in the high NLR group and the low NLR group were compared. During a median follow-up period of 46.4 months, 58 patients (45.0%) experienced relapse. The cumulative relapse-free rate was significantly higher in the low NLR group than in the high NLR group (P = 0.03, log-rank test). Multivariate analysis identified high NLR as an independent prognostic factor for clinical relapse (hazard ratio, 1.74; 95% confidence interval, 1.02-2.98; P = 0.04). NLR is a novel and useful predictor of clinical relapse in UC patients with MH, and it can potentially be a strong indicator to determine the appropriate treatment strategy and decision-making in clinical practice.

Esophageal mast cells may be associated with the perception of symptoms in patients with eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is a type 2 helper T-cell (Th2)-mediated allergic disease that involves mast cells. This study aimed to clarify the relationship between perception of symptoms and mast cell levels in patients with EoE. METHODS: We enrolled patients with asymptomatic esophageal eosinophilia (aEE) and those with symptomatic EoE. Immunofluorescence staining was performed on esophageal biopsy specimens to quantify mast cell-related molecules, such as tryptase, proteinase-activated receptor (PAR)-2, and vasoactive intestinal peptide receptor (VPAC)-1. RESULTS: We evaluated 28 and 58 patients with aEE and EoE, respectively. There were no significant differences in clinical and endoscopic features and peak eosinophil counts between both groups. Mast cell tryptase-positive areas were significantly higher in EoE than in aEE (4.9 [3.5-6.2] vs. 2.0 [1.2-3.4] %, p < 0.01). The number of PAR-2-positive cells was significantly higher in EoE than in aEE (14 [8.8-20.0] vs. 4 [2.8-8.0] cells/high-power field [HPF], p < 0.01). The number of VPAC-1-positive cells was significantly higher in the EoE group than in the aEE group (13 [8.8-16.0] vs. 6 [3.0-9.3] cells/HPF, p < 0.01). A positive correlation was observed between the numbers of PAR-2-positive cells and VPAC-1-positive cells (r = 0.851, p < 0.01). Moreover, mast cell tryptase-positive areas positively correlated with the number of PAR-2- and VPAC-1-positive cells (r = 0.352, p < 0.01; r = 0.355, p < 0.01, respectively). CONCLUSIONS: Esophageal mast cells and their receptors, PAR-2 and VPAC-1, may contribute to the perception of symptoms in patients with EoE.

Analysis of autonomic function during natural defecation in patients with irritable bowel syndrome using real-time recording with a wearable device.

BACKGROUND: Autonomic dysfunction is a factor in irritable bowel syndrome (IBS). However, there are no reports of autonomic nervous system (ANS) activity during natural defecation in patients with IBS. We aimed to clarify the relationship between ANS activity and life events, such as defecation and abdominal symptoms, using real-time recording. METHODS: Six patients with IBS and 14 healthy controls were enrolled in this prospective multicenter study. ANS activity was recorded for 24 h using a T-shirt wearable device, and life events were recorded simultaneously in real time using a smartphone application software. Low frequency/high frequency (LF/HF) and HF calculated by power spectrum analysis were defined as activity indicators of the sympathetic and parasympathetic nerves, respectively. RESULTS: The means of LF/HF and HF in the period with positive symptoms were comparable between the groups; however, the sum of LF/HF, sum of ΔLF/HF, and the maximum variation in ΔLF/HF were significantly higher in the IBS group. In the IBS group, the sum of ΔLF/HF and LF/HF increased significantly from 2 min before defecation, and the sum of LF/HF remained significantly higher until 9 min after defecation. The sum of ΔLF/HF at 2 min before defecation was significantly positively correlated with the intensity of abdominal pain and diarrhea and constipation scores. In contrast, it was significantly negatively correlated with defecation satisfaction and health-related quality of life. CONCLUSIONS: In patients with IBS, sympathetic nerve activity was activated 2 min before defecation, which was correlated with abdominal symptoms and lower QOL.

[Current real-world treatments for Japanese patients with eosinophilic esophagitis].

A total of 306 patients with eosinophilic esophagitis (EoE) were analyzed at our department. Proton pump inhibitors or potassium-competitive acid blockers were used as the first-line treatment in 286 (93.5%) patients. Fifty-five (18.0%) patients received topical steroid swallowing therapy. During 17.7-month mean follow-up, 46.4% of the patients were followed-up with no medications, 37.3% of the patients received maintenance or on-demand therapy using acid-suppressive drugs, and 9.8% of the patients received maintenance therapy with steroid swallowing. The majority of patients with EoE were treated using a therapeutic strategy similar to that used for gastroesophageal reflux disease. However, some patients were refractory to the treatment. Current real-world treatment strategies for Japanese patients with EoE are clarified.

Psychological Stress Exacerbates Inflammation of the Ileum via the Corticotropin-Releasing Hormone-Mast Cell Axis in a Mouse Model of Eosinophilic Enteritis.

The effects of psychological stress on eosinophilic gastrointestinal disorders have not been elucidated. This study investigated the effects of psychological stress in a mouse model of eosinophilic enteritis (EoN). BALB/c mice were treated with ovalbumin (OVA) to create an EoN model and subjected to either water avoidance stress (WAS) or sham stress (SS). Microscopic inflammation, eosinophil and mast cell counts, mRNA expression, and protein levels of type 2 helper T cell (Th2) cytokines in the ileum were compared between groups. We evaluated ex vivo intestinal permeability using an Ussing chamber. A corticotropin-releasing hormone type 1 receptor (CRH-R1) antagonist was administered before WAS, and its effects were analyzed. WAS significantly increased diarrhea occurrence and, eosinophil and mast cell counts, and decreased the villus/crypt ratio compared to those in the SS group. The mRNA expression of CRH, interleukin IL-4, IL-5, IL-13, eotaxin-1, and mast cell tryptase ß2 significantly increased, and the protein levels of IL-5, IL-13, and OVA-specific immunoglobulin E (IgE) also significantly increased in the WAS group. Moreover, WAS significantly increased the intestinal permeability. The CRH-R1 antagonist significantly inhibited all changes induced by WAS. Psychological stress exacerbated ileal inflammation via the CRH-mast cell axis in an EoN mouse model.