Toll-Like Receptor 7-Expressed Macrophages Are Involved in the Pathogenesis of Esophageal Achalasia and Esophagogastric Junction Outflow Obstruction.

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 Promotes the Fusion of Autophagolysosomes and Prevents Excessive Inflammasome Activation in Dextran Sulfate Sodium-Induced Colitis.

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-1ß 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.

Gastric Focal Neutrophil Infiltration and Wide Duodenal Gastric Foveolar Metaplasia Are Histologic Discriminative Markers for Crohn's Disease and Behçet's Disease.

BACKGROUND/AIMS: Behçet's disease (BD) with intestinal lesions and Crohn's disease (CD) share clinical features. However, no report has compared the 2 diseases with regard to lesions of the upper gastrointestinal tract (UGT). We aimed to evaluate endoscopic and histologic findings of UGT in CD and BD. METHODS: We retrospectively assessed the endoscopic records and biopsy samples of 84 Helicobacter pylori-negative patients (50 CD, 34 BD). In duodenal samples, MUC5AC immunohistochemical analysis was performed to identify gastric foveolar metaplasia. RESULTS: In endoscopic findings, bamboo joint-like appearance (17/50 CD, 0/34 BD) and erosions (14/50 CD, 2/34 BD) were significantly more frequent in CD gastric lesions (p < 0.001, and p = 0.012). In histologic findings of stomach, focal neutrophil infiltration in lamina propria (15/48 CD, 1/34 BD) was significantly more frequent in CD (p < 0.001). In that of duodenum, wide gastric foveolar metaplasia (19/49 CD, 1/34 BD) was significantly more frequent in CD duodenal lesions (p = 0.013). The mean maximum width of the gastric foveolar metaplasia was 114.0 ± 10.6 and 29.5 ± 4.5 µm for CD and BD respectively (p = 0.003). CONCLUSIONS: In H. pylori-negative patients, gastric focal neutrophil infiltration and wide duodenal gastric foveolar metaplasia were important for distinguishing CD from BD.

Successful adalimumab treatment and usefulness of capsule endoscopy for gut inflammation concomitant with ankylosing spondylitis.

Here we describe a 20-year-old man with ankylosing spondylitis and gut inflammation, who was successfully treated with adalimumab. Capsule endoscopy and ileocolonoscopy showed multiple erosions and aphthoid ulcers in the ileum and the ileocecal valve. Immunohistochemical analysis of the terminal ileum demonstrated that the number of IL-23p19 expressing macrophages was increased. Adalimumab was administered, and his back pain and abdominal symptoms improved. Adalimumab might be an effective treatment for gut inflammation related to ankylosing spondylitis.

Prediction of maintained mucosal healing in patients with Crohn's disease under treatment with infliximab using diffusion-weighted magnetic resonance imaging.

BACKGROUND: Maintenance of mucosal healing may lead to a better outcome in patients with Crohn's disease (CD). Magnetic resonance diffusion-weighted imaging (MR-DWI) scans 1 year after infliximab (IFX) induction therapy were assessed as predictors of maintained response, or remission, through 3 years of treatment in patients with CD. SUMMARY: MR-DWI and endoscopy data were prospectively collected throughout IFX treatment. Altogether, 86 lesions from 13 patients given IFX as induction (weeks 0, 2 and 6) and maintenance (5 mg/kg every 8 weeks beginning at week 14) therapy were analyzed with MR-DWI for 0.5-1.5 years from the starting point. Mucosal findings were confirmed by endoscopy at 1 and 3 years (gold standard). Of the 86 lesions, 65 were graded '0' and 21 were graded '1' based on their hyperintensity (HI; or lack thereof) on MR-DWI. Two years after the first evaluation, 7 of 15 false-negative lesions had turned positive based on colonoscopy findings, and 60 of 62 true-negative lesions had not. Thus, 0.03% of those predicted to remain in remission had relapsed (negative predictive value 0.9677, p < 0.0001). MR-DWI-HI at 1 year coincided with the presence of endoscopic inflammation, with sensitivity of 66.67%, specificity of 80.52%, and an area under the curve (AUC) value of 0.7359 (0.5479-0.9240, p = 0.0211). The AUC value of MR-DWI-HI at 3 years was 0.8402 (0.7460-0.9343, p = 0.001) with sensitivity of 94.12% and specificity of 73.91%. KEY MESSAGE: A definition of the response on the basis of MR-DWI-HI might be helpful for optimizing treatment for patients with CD under treatment with IFX.

Evaluation of Crohn's Disease Small-Bowel Mucosal Healing Using Capsule Endoscopy and Usefulness of Leucine-Rich α2-Glycoprotein.

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.

Bacterial exposure risk to the endoscopist's face while performing endoscopy.

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.

A Logistic Regression Model for Predicting the Risk of Subsequent Surgery among Patients with Newly Diagnosed Crohn's Disease Using a Brute Force Method.

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.

Molecular design, synthesis, and evaluation of novel potent apoptosis inhibitors inspired from bongkrekic acid.

Bongkrekic acid (BKA) is an inhibitor of adenine nucleotide translocase (ANT). Since inhibition of ANT is connected to the inhibition of cytochrome c release from mitochondria, which then results in the suppression of apoptosis, it has been used as a tool for the mechanistic investigation of apoptosis. BKA consists of a long carbon chain with two asymmetric centers, a nonconjugated olefin, two conjugated dienes, three methyl groups, a methoxyl group, and three carboxylic acids. This complicated chemical structure has caused difficulties in synthesis, supply, and biochemical mechanistic investigations. In this study, we designed and synthesized more simple tricarboxylic acids that were inspired by the molecular structure of BKA. Their cytotoxicity and apoptosis-preventing activity in HeLa cells and the effect on the mitochondrial inner membrane potential (ΔΨm) in HL-60 cells were then evaluated. All tested tricarboxylic acid derivatives including BKA showed little toxicity against HeLa cells. BKA and two of the synthesized derivatives significantly suppressed staurosporine (STS)-induced reductions in cell viability. Furthermore, STS-induced ΔΨm collapse was significantly restored by pretreatment with BKA and a tricarboxylic acid derivative. Other derivatives, in which one of three carboxylic acids was esterified, exhibited potent toxicity, especially a derivative bearing a carbon chain of the same length as that of BKA. In conclusion, we have developed a new lead compound as an apoptosis inhibitor bearing three carboxylic acids connected with the proper length of a long carbon chain.

Tacrolimus Up-regulates Expression of TGFß Receptor Type II via ERK, Providing Protection Against Intestinal Epithelial Injury.

BACKGROUND/AIM: Transforming growth factor ß (TGFß) signaling plays a key role in modulating intestinal epithelial cell (IEC) homeostasis. The present study aimed to investigate the direct effect of tacrolimus on TGFß signaling in IECs. MATERIALS AND METHODS: The protective effects of tacrolimus, with or without anti-TGFß antibody, in dextran sulfate sodium (DSS)-induced colitis were evaluated. RESULTS: Tacrolimus ameliorated IEC apoptosis-mediated mucosal destruction despite anti-TGFß treatment. TGFß receptor type II (TGFß-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-TGFß treatment. Moreover, tacrolimus induced TGFß-RII up-regulation through ERK activation. CONCLUSION: Our data indicate that tacrolimus directly activated TGFß-SMAD signaling via the ERK pathway in IECs, thereby providing protection against apoptosis-mediated intestinal epithelial injury.

Automated evaluation of colon capsule endoscopic severity of ulcerative colitis using ResNet50.

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.

Long-term efficacy and tolerability of dose-adjusted thiopurine treatment in maintaining remission in inflammatory bowel disease patients with NUDT15 heterozygosity.

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 thiopurineinduced 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.

Endoscopic and histopathologic features of Anti-PD-1-related collagenous colitis.

Objectives: Cancer 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. Methods: This 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. Results: All 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. Conclusions: Anti-programmed cell death-1-related collagenous colitis is reversible; appropriate diagnosis of adverse events is crucial for the continuation of immune checkpoint inhibitor therapy.

Influence of Esophageal Endoscopic Submucosal Dissection on the Changes of Energy Metabolism during the Perioperative Period.

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.

Isolated myelitis in a patient with Behcet's disease during golimumab therapy.

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.

An undiagnosed patient with skin rash, polyarthritis, and edema responding to low-dose colchicine: A case report.

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.

The utility of two-dimensional real-time shear wave elastography for assessing liver fibrosis in patients with chronic hepatitis C virus infection.

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.

Esophageal achalasia with mucosal damage due to enteric-coated aspirin.

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.

Case report of lanthanum deposition in the esophagus.

A 69-year-old woman had received hemodialysis for chronic renal failure and was taking lanthanum carbonate since 63 years of age. She presented with appetite loss and nausea. We performed esophagogastroduodenoscopy, which revealed multiple longitudinal white plaques in the esophagus. Lesion biopsies showed lanthanum deposition, and lanthanum carbonate was found histologically by energy-dispersive X-ray spectroscopy. The plaques of this patient appeared like those of dabigatran-induced esophagitis, and may have occurred due to long-term contact of the esophageal epithelium with lanthanum carbonate because patient spent time in lying state. Although a few studies regarding lanthanum deposition in the stomach have been conducted, there are no reports on lanthanum deposition in the esophagus. This case suggests that the presence of longitudinal white plaques in the esophagus may indicate lanthanum deposition.

A case of nivolumab-associated colitis, which relapsed after mucosal healing and was then successfully treated with mesalazine.

Currently, the number of patients treated with immune-checkpoint inhibitor involving nivolumab is increasing. Nevertheless, it causes various immune-related adverse events (irAEs). Here, we report the case of a patient who underwent long-term follow-up after suffering from nivolumab-associated colitis. The patient was a 57-year-old man who underwent resection of a bladder tumor. Following surgery, lymph node metastasis was detected, and he was treated by nivolumab. Two months after treatment with nivolumab, the patient complained of bloody diarrhea. Colonoscopy revealed pancolitis with erosions, loss of vascular pattern and erythema. Pathological findings indicated a disease state of pan-ulcerative colitis. As an irAE by nivolumab, the patient was started with 30 mg of prednisolone. Prednisolone treatment successfully induced clinical remission and mucosal healing. Nevertheless, eight months after stopping the steroid treatment, the colitis relapsed with diarrhea following elevation of fecal immunochemical test (FIT) and fecal calprotectin (CPT). The relapsed colitis was treated by mesalazine, and then diarrhea was improved. Nivolumab-associated colitis relapsed following mucosal healing suggesting that it is necessary to consider maintenance therapy as well as remission induction for long-term survivor. The present case also demonstrates that the FIT and CPT would be effective biomarker to assess the disease activity of nivolumab-associated colitis.