Despite the availability of several biologics for ulcerative colitis (UC), there remains a critical need to identify first-line treatment biologics. The superiority of infliximab (IFX) over vedolizumab (VED) and ustekinumab (UST) was evaluated as initial UC treatments in patients with biologic-naïve UC. This multicenter, randomized control trial was conducted across 20 Japanese medical institutions. An independent center randomly allocated patients with UC (Mayo score ≥ 6) who had not previously used biologics to three treatment groups (IFX, VED, UST). The primary endpoint was the clinical remission (CR) rate at week 12, with other endpoints including the treatment continuation rate at week 26 and adverse events (AEs). From May 2021 to June 2023, 107 cases were registered, including 104 for safety and 97 for efficacy evaluation. CR rate at week 12 was 36.4 https://jrct.niph.go.jp/ ).

INTRODUCTION:Esophageal achalasia is a typical esophageal motility disorder (EMD). Although viral infections have been hypothesized to play a role in the pathogenesis of esophageal achalasia, its etiology remains unclear. This study used esophageal muscle layer specimens collected during per-oral endoscopic myotomy (POEM) procedures to investigate the association between esophageal achalasia and esophagogastric junction outflow obstruction (EGJOO) and pattern recognition receptors. METHODS:Patients with esophageal achalasia and EGJOO who underwent POEM were allocated to the EMD group. Biopsies of the inner circular muscle were conducted during the POEM procedure. The control group comprised individuals diagnosed with esophageal squamous cell carcinoma who underwent surgical resection. Expression of pattern recognition receptors, including Toll-like receptor (TLR) 7, was examined by polymerase chain reaction. Immunohistochemical staining was performed to determine TLR7 expression sites in the esophageal muscle layer, and the relationship between TLR7 mRNA expression and clinical score was investigated. RESULTS:Our analysis revealed a notable upregulation of TLR7 mRNA levels within the muscle layer of esophageal achalasia and EGJOO, in contrast to those of control specimens. In contrast, the correlation between TLR7 and clinical score was not significant. Immunohistochemical staining revealed increased numbers of TLR7-expressing macrophages between the muscle layers. CONCLUSIONS:TLR7-expressing macrophages are involved in the innate immune response underlying esophageal achalasia and EGJOO. This result will lead to the elucidation of new pathogenetic mechanisms and the development of novel therapeutic targets.

Vitamin A ensures intestinal homeostasis, impacting acquired immunity and epithelial barrier function; however, its role in innate immunity is mostly unknown. Here, we studied the impact of vitamin A in different dextran sulfate sodium (DSS)-induced colitis animal models. Interestingly, more severe DSS-induced colitis was observed in vitamin A-deficient (VAD) mice than in vitamin A-sufficient (VAS) mice; the same was observed in VAD severe combined immunodeficient mice lacking T/B cells. Remarkably, IL-1β production, LC3B-II expression, and inflammasome activity in the lamina propria were significantly elevated in VAD mice. Electron microscopy revealed numerous swollen mitochondria with severely disrupted cristae. In vitro, non-canonical inflammasome signaling-induced pyroptosis, LC3B-II and p62 expression, and mitochondrial superoxide levels were increased in murine macrophages (RAW 264.7) pretreated with retinoic acid receptor antagonist (Ro41-5253). These findings suggest that vitamin A plays a crucial role in the efficient fusion of autophagosomes with lysosomes in colitis.

Recently, the importance of achieving clinical and deep remissions with mucosal healing (MH) has been demonstrated as a therapeutic goal to avoid Crohn's disease (CD) surgical operations. Although ileocolonoscopy (CS) is considered the gold standard, there are increasing reports on the benefits of capsule endoscopy (CE) and serum leucine-rich α2-glycoprotein (LRG) for evaluating small-bowel lesions in CD. We evaluated the data of 20 patients with CD who underwent CE in our department between July 2020 and June 2021 and whose serum LRG level was measured within 2 months. Concerning the mean LRG value, there was no significant difference between the CS-MH and CS-non-MH groups. Conversely, the mean LRG level was 10.0 μg/mL in seven patients in the CE-MH group and 15.2 μg/mL in 11 patients in the CE-non-MH group with a significant difference between the two groups (p = 0.0025). This study's findings show that CE can sufficiently determine total MH in most cases, and LRG is useful for evaluating CD small-bowel MH because of its correlation with CE-MH. Furthermore, satisfying CS-MH criteria and a cut-off value of 13.4 μg/mL for LRG suggests its usefulness as a CD small-bowel MH marker, which could be incorporated into the treat-to-target strategy.

Surgery avoidance is an important goal in Crohn’s disease (CD) treatment and predicting the risk of subsequent surgery is important to determine adequate therapeutic strength for patients with newly diagnosed CD. Herein, we aimed to construct a prediction model for the risk of subsequent surgery based on disease characteristics at the patients’ initial visit. We retrospectively collected disease characteristic data from 93 patients with newly diagnosed CD. A logistic regression model with a brute force method was used to maximize the area under the receiver operating characteristic curve (auROC) by employing a combination of potential predictors from 14 covariates (16,383). The auROC remained almost constant when one to 12 covariates were considered, reaching a peak of 0.89 at four covariates (small-bowel patency, extensive small-bowel lesions, main lesions, and the number of poor prognostic factors), and it decreased with increasing covariate size. The most significant predictors were small-bowel patency, extensive small-bowel lesions, and age or major lesions. Therefore, this prediction model using covariates may be helpful in determining the likelihood that a patient with newly diagnosed CD will require surgery, which can aid in appropriate treatment selection for high-risk patients.

Abstract Objectives This study aimed to clarify the disinfectant efficacy of the 222‐nm far ultraviolet‐C (UV‐C) during esophagogastroduodenoscopy using bacterial cultures. Methods The endoscopists performed esophagogastroduodenoscopy wearing a gown with a tryptic soy agar medium plate on their epigastric region and were divided into two groups: 222‐nm far UV‐C irradiation (UV group) and non‐UV irradiation (non‐UV group). As a control group, tryptic soy agar medium plates were placed about 110 cm above the floor. The incidence of bacterial contamination was determined by positive bacterial culture. The cultured bacteria were identified by 16S rRNA sequencing. Additionally, the actual UV exposure dose was measured using the UV‐indicator card which changed colors upon exposure to 222 nm far UV‐C. Results The bacterial culture positivity in the UV group (5.03%) was significantly lower than that in the non‐UV group (25.76%), p < 0.0001. Most of the bacteria identified in the UV and non‐UV groups were normal constituents of the oral flora, including Streptococcus salivarius and Staphylococci. Conversely, pathogenic microbes were found in the control group. The actual exposure doses of 222‐nm far UV‐C at the endoscopists’ face, neck, and epigastric region were 2.09 ± 0.29, 5.89 ± 0.49, and 7.36 ± 0.58 mJ/cm2, respectively. Conclusions The 222‐nm far UV‐C irradiation reduced bacterial contamination for endoscopists. It can be used with conventional physical coverings to provide more effective infection control.

Objectives: Gastrointestinal endoscopy increases the risk of bacterial exposure to endoscopists. However, before 2019, most endoscopists did not pay attention to microorganism transmission from patients. This study aimed to investigate the incidence of bacterial exposure to endoscopists' faces during gastrointestinal endoscopic procedures using the bacterial culture method. Methods: This was a single-centered, retrospective study including endoscopists who performed various gastrointestinal endoscopy procedures at the Division of Endoscopy, Hirosaki University Hospital between August 31 and October 6, 2020. Endoscopists wore surgical masks and affixed pre-sterilized films over them. Following the gastrointestinal endoscopic procedures, attached microbes were collected from the endoscopists' surface films using sterilized swabs. Collected microorganisms were cultured on tryptic soy agar and 5% sheep blood agar, and the incidence of bacterial exposure was determined by bacterial culture positivity. Cultured bacteria were identified by gram staining and 16S rRNA gene sequencing. Results: Bacterial culture positivity was 12.6%, and it was significantly higher in therapeutic than in diagnostic endoscopy. Notably, therapeutic endoscopy increased bacterial culture positivity in colonoscopy, but not in esophagogastroduodenoscopy. Staphylococci, including Staphylococcus epidermidis and Staphylococcus capitis, were the most commonly found bacteria in samples identified through 16S rRNA gene sequencing. Conclusions: The risk of bacterial exposure to the endoscopist's face was increased in colonoscopy treatment procedures. Therefore, endoscopists should be aware of the significant risk of microbial infection from scattering fluid that comes from the endoscopy's working channel.

Background/Aim: Transforming growth factor /i (TGF/i) signaling plays a key role in modulating intestinal epithelial cell (IEC) homeostasis. The present study aimed to investigate the direct effect of tacrolimus on TGF/i signaling in IECs. Materials and Methods: The protective effects of tacrolimus, with or without anti-TGF/i antibody, in dextran sulfate sodium (DSS)-induced colitis were evaluated. Results: Tacrolimus ameliorated IEC apoptosis-mediated mucosal destruction despite anti-TGF/i treatment. TGF/i receptor type II (TGF/i-RII), phosphor-SMAD family members 2/3, and phosphor-extracellular signal-regulated kinase (ERK) expression in IECs was enhanced in tacrolimus-treated mice, and these positive effects were maintained despite anti-TGF/i treatment. Moreover, tacrolimus induced TGF/i-RII up-regulation through ERK activation. Conclusion: Our data indicate that tacrolimus directly activated TGF/i???SMAD signaling via the ERK pathway in IECs, thereby providing protection against apoptosis-mediated intestinal epithelial injury.

Capsule endoscopy has been widely used as a non-invasive diagnostic tool for small or large intestinal lesions. In recent years, automated lesion detection systems using machine learning have been devised. This study aimed to develop an automated system for capsule endoscopic severity in patients with ulcerative colitis along the entire length of the colon using ResNet50. Capsule endoscopy videos from patients with ulcerative colitis were collected prospectively. Each single examination video file was partitioned into four segments: the cecum and ascending colon, transverse colon, descending and sigmoid colon, and rectum. Fifty still pictures (576 × 576 pixels) were extracted from each partitioned video. A patch (128 × 128 pixels) was trimmed from the still picture at every 32-pixel-strides. A total of 739,021 patch images were manually classified into six categories: 0) Mayo endoscopic subscore (MES) 0, 1) MES1, 2) MES2, 3) MES3, 4) inadequate quality for evaluation, and 5) ileal mucosa. ResNet50, a deep learning framework, was trained using 483,644 datasets and validated using 255,377 independent datasets. In total, 31 capsule endoscopy videos from 22 patients were collected. The accuracy rates of the training and validation datasets were 0.992 and 0.973, respectively. An automated evaluation system for the capsule endoscopic severity of ulcerative colitis was developed. This could be a useful tool for assessing topographic disease activity, thus decreasing the burden of image interpretation on endoscopists.

AbstractObjectivesCancer patients treated with immune checkpoint inhibitors occasionally show persistent diarrhea accompanied by endoscopic features of ulcerative colitis. The endoscopic mucosal inflammation may appear mild in some patients compared to the clinical severity, which can make choosing a treatment challenging. In this study, we evaluated the factors that support the continuation of chemotherapy by assessing the endoscopic and histopathological characteristics of patients who experienced diarrhea after immune checkpoint inhibitor administration.MethodsThis study included eight patients who were diagnosed with collagenous colitis based on pathological assessments. We retrospectively investigated these patients’ backgrounds, laboratory data, and computed tomography images that were extracted from their medical records. We also summarized their endoscopic and pathologic findings.ResultsAll eight patients were being treated with anti‐programmed cell death‐1/programmed cell death‐ligand 1 therapeutic agents and had a recent history of oral proton pump inhibitor therapy. The anti‐programmed cell death‐1‐related collagenous colitis in these cases was characterized by endoscopically mild mucosal inflammation, high fecal calprotectin levels, and a lower frequency of intestinal wall thickening on computed tomography. Histological assessments showed CD8+ lymphocytes predominantly infiltrating the lamina propria and crypts of the colonic mucosa. Suspending the proton pump inhibitor therapy relieved the patients’ symptoms and allowed the continuation of the anti‐programmed cell death‐1/programmed cell death‐ligand 1 therapy.ConclusionsAnti‐programmed cell death‐1‐related collagenous colitis is reversible; appropriate diagnosis of adverse events is crucial for the continuation of immune checkpoint inhibitor therapy.

Background/Aims Thiopurines are key drugs for inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD). Recently, NUDT15 polymorphism (R139C, c.415C > T) has been shown to be associated with thiopurine-induced adverse events in Asian populations. In patients with the C/T genotype, low-dose thiopurine treatment is recommended, but its long-term efficacy and tolerability remain unclear. This study aimed to uncover the long-term efficacy and appropriate dosage of thiopurine for IBD patients with the C/T genotype. Methods A total of 210 patients with IBD (103 UC and 107 CD) determined to have NUDT15 R139C variants were enrolled. Clinical data were retrospectively reviewed from medical records. Results Of 46 patients (21.9%) with the C/T genotype, 30 patients (65.2%) were treated with thiopurines. Three of whom (10.0%) discontinued thiopurine treatment due to adverse events and 27 of whom continued. The median maintenance dosage of 6-mercaptopurine was 0.25 mg/kg/day (range, 0.19–0.36 mg/kg/day), and 6-thioguanine nucleotides level was 230 (104–298) pmol/8 × 108 red blood cells. Cumulative thiopurine continuation rates for 120 months for patients with the C/C and C/T genotypes were not significantly different (P = 0.895). Cumulative non-relapse rates in the patients with UC treated with thiopurine monotherapy and surgery-free rates in CD patients treated with combination therapy (thiopurines and anti-tumor necrosis factor-α agents) for maintenance remission were not significantly different at 60 months (C/C vs. C/T, P = 0.339 and P = 0.422, respectively). Conclusions Low-dose thiopurine treatment is an effective and acceptable treatment for patients with C/T genotype.

Esophageal endoscopic submucosal dissection (ESD) is considered to be more complex than gastric ESD. This study aimed to assess the physical invasiveness of esophageal ESD during perioperative periods by measuring resting energy expenditure (REE). The factors affecting REE that could be used to identify patients requiring perioperative management were also investigated. Overall, 75 patients who had undergone esophageal ESD were prospectively enrolled. REE, body weight, and basal energy expenditure were measured on the day of and the day following ESD. The mean REE/body weight was 20.2 kcal/kg/day on the day of ESD and significantly increased to 23.0 kcal/kg/day one day after ESD. The stress factor on the day after ESD was 1.11. White blood cell, neutrophil, and C-reactive protein levels increased on the day after ESD and correlated with the changes in REE. Among the factors including age, body mass index, total resection area, operation time, and sarcopenia, only the total resection area was associated with changes in REE. In conclusion, energy metabolism increases during the perioperative period for esophageal ESD. The increase in the stress factor for esophageal ESD was higher than that in gastric and colorectal ESD. Furthermore, patients with large resection areas require greater attention in perioperative management.

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD) are LPDs occurring in the use of immunosuppressive agents other than organ transplantations. It is supposed that disease origin might be various such as used medicines, aging, immune abnormality of collagen disease, chronic inflammation, but details are still unclear. We retrospectively analyzed the relationships between clinicopathological features of OIIA-LPD patients and prognosis in our institute. Twenty-nine OIIA-LPD patients who have visited our department from April 2011 to July 2020 are analyzed. All patients discontinued immunosuppressants at the diagnosis. Patients are consisted by 9 males and 20 females, aged 24-83 y.o. (median 67 y.o.), histologically 12 diffuse large B-cell lymphoma, 6 classical Hodgkin lymphoma, 4 polymorphic PTLD, etc., 27 rheumatoid arthritis and 2 systemic lupus erythematosus in background diseases. Firstly, the effect of clinical features on overall survival was estimated by univariate and multivariate analysis in all patients. Secondary we studied which factors determined the need for any therapies by Fisher's exact test. Poor performance status, B symptoms, advanced clinical stage, elevated CRP, higher sIL-2R were significantly worsened the prognosis in univariate analysis but only B symptoms, elevated CRP, higher sIL-2R were independent prognostic factor in multivariate analysis. Seven out of 29 patients have experienced a regression of OIIA-LPD by withdrawal of immunosuppressants without cytotoxic therapy and CRP was only factors which differed statistically between treated and untreated groups. B symptoms, CRP and sIL2R were correlated with the prognosis of OIIA-LPD patients in our study. But this study is a single-center, retrospective and small number analysis, so that this result was very limited. Multicenter and prospective studies are warranted in the future.

A 54-year-old man was referred to our hospital with painful rashes on the extremities. He also developed polyarthritis and pitting pedal edema. Blood tests showed no specific autoantibodies and were negative for human leukocyte antigens B51, B15, and B27. Lower extremity venous ultrasonography and computed tomography angiography showed no vascular disorders. Skin biopsy showed no evidence of thrombosis or vasculitis. Direct fluorescence antibody analysis showed no antibody or complement deposition. Joint ultrasonography showed mild synovial thickening and/or synovial effusion in the extremities. Non-steroidal anti-inflammatory drugs and topical steroids were administered, followed by oral steroids. However, the signs and symptoms did not improve. Oral steroids were discontinued, and colchicine (0.5 mg/day) was administered. Thereafter, the symptoms of arthritis improved, and no skin rash developed. In potentially inflammatory conditions with skin rash, edema, and polyarthritis that are difficult to diagnose, low-dose colchicine administration may be considered for prompt relief of symptoms.

A 76-year-old man was referred to our hospital for examination and treatment of dysphagia. He has been taking enteric-coated aspirin for myocardial infarction. Esophagogastroduodenoscopy (EGD) revealed the presence of esophageal ulcers in the distal esophagus and five to six tablets of enteric-coated aspirin. The esophageal ulcers were believed to have been caused by the retention of aspirin within the esophagus due to achalasia. We substituted enteric-coated aspirin with powdered aspirin. A follow-up EGD performed 1 month later showed improvement of esophageal mucosa. The patient was diagnosed with type I achalasia. Per-oral endoscopic myotomy was performed, and his symptoms improved after the procedure. Although a few studies have investigated the direct effect of aspirin, none of them has reported on the direct effect of aspirin on the esophagus. It might be effective to administer powdered aspirin for patients with achalasia to prevent esophageal ulcers caused by the direct effect of aspirin.

Tumor necrosis factor-alpha (TNF-α) inhibitors are increasingly used for various autoimmune diseases. Demyelinating events in the CNS, including myelitis, are reportedly associated with TNF-α inhibitor exposure. Behcet's disease rarely involves the spinal cord. A 51-year-old Japanese woman presented with back pain, leg weakness, and numbness during golimumab administration, a TNF-α inhibitor, for Behcet's disease. Magnetic resonance imaging revealed multifocal myelitis in the cervical and thoracic spinal cords. Discontinuation of golimumab and steroid therapy were effective and the symptoms have not relapsed. Although it is possible that the patient's myelitis was part of the symptoms of neuro-Behcet's disease, we believe that golimumab likely played a role in the myelitis development.

Objective Two-dimensional shear wave elastography (2D-SWE) is a new ultrasound-based elastography method to evaluate liver fibrosis in the daily practice. However, the utility of 2D-SWE among the other liver fibrosis markers is unclear. Methods We enrolled 141 consecutive patients with hepatitis C virus infection, 66 men and 75 women (median age, 67 years), who underwent liver biopsy and 2D-SWE (LOGIQ E9, GE Healthcare, Wauwatosa, WI, USA). We compared the diagnostic accuracy of the 2D-SWE with those of magnetic resonance elastography (MRE; MR-Touch, GE Healthcare, Milwaukee, WI, USA), Mac-2 binding protein glycosylation isomer (M2BPGi), fibrosis-4 index (FIB-4) and platelet counts (PLT), using the histologic METAVIR scoring as the reference standard. Results The areas under the receiver operating characteristics curves (AUROCs) of 2D-SWE, MRE, M2BPGi, FIB-4 and PLT for ≥F2, ≥F3 and F4 were 0.86, 0.88, 0.79, 0.81 and 0.77; 0.92, 0.93, 0.86, 0.87 and 0.83; and 0.91, 0.97, 0.85, 0.85 and 0.82, respectively. For diagnosing ≥F2 and ≥F3, the AUROCs of 2D-SWE and those of MRE showed no significant differences, and both 2D-SWE and MRE showed significantly higher AUROCs than the other markers. For diagnosing F4, the AUROC of MRE was significantly higher than those of other fibrosis markers. Conclusion 2D-SWE has an excellent diagnostic accuracy equivalent to that of MRE for assessing significant (≥F2) and severe (≥F3) fibrosis. MRE demonstrated a higher AUROC than 2D-SWE, but this last one has advantages such as lower cost, fewer contraindications and greater ease of performance than MRE.

Myelodysplastic syndromes (MDSs) are a group of myeloid neoplasms characterized by blood cell deformation and dysfunction, and MDS with trisomy 8 is closely linked with intestinal Behçet’s-like diseases. Intestinal Behçet’s-like disease is refractory to conventional therapies, including prednisolone, immunomodulators, and anti-tumor necrosis factor α agents. Here, we describe a 56-year-old woman with intestinal Behçet’s-like disease ascribed to MDS with trisomy 8 who had multiple intractable intestinal ulcers. She presented with periodic fever and abdominal pain. The genetic analysis showed a heterozygous E148Q mutation in the Mediterranean fever gene. The patient did not tolerate treatment with colchicine because of diarrhea; therefore, azacitidine therapy was initiated. One cycle of azacitidine therapy improved the multiple intestinal ulcers, and the periodic fever and abdominal pain gradually disappeared. After eight cycles of azacitidine therapy, ileocolonoscopy, histological assessment and capsule endoscopy revealed mucosal healing. Azacitidine therapy was continued, and mucosal healing was maintained for more than 2 years. This case suggests that azacitidine therapy which has immunoregulatory effects and epigenetic modulations, might control intestinal Behçet’s-like disease associated with MDS involving trisomy 8.

Fever of unknown origin (FUO) is caused by various diseases, making differential diagnosis difficult. This study aimed to determine the clinical features of patients with FUO for use in daily medical practice. Medical records of patients who first visited our department for FUO between January 2008 and December 2017 were reviewed. We classified the diagnostic categories as infection, non-infectious inflammation, neoplasm, others, and unidentified through definitive diagnosis and compared the clinical characteristics of patients who fulfilled the criteria of classical FUO and those who did not. The most prevalent diseases in patients who fulfilled the criteria were adult-onset Still’s disease, Behçet’s disease (BD), and polymyalgia rheumatica, which do not have any specific image inspection or specific serological markers. BD and familial Mediterranean fever were most prevalent in patients who did not fulfill the criteria. All neoplasms fulfilled the criteria of classical FUO. The most useful diagnostic procedure was determined according to the criteria of each disease. The key factor that did not fulfill the criteria was periodic fever continuing for less than 3 weeks. When examining patients with FUO, we should strictly diagnose in accordance with the criteria of each disease and consider diseases that cause periodic fever.