Clinical performance of fecal calprotectin, lactoferrin, and hemoglobin for evaluating the disease activity of IBD and detecting colorectal tumors.

Background and Aim: Recently, noninvasive fecal markers have been used as indicators of intestinal inflammation in patients with inflammatory bowel disease (IBD). We conducted a clinical validation study to measure fecal calprotectin (Cp), lactoferrin (Lf), and hemoglobin (Hb) levels using an all-in-one kit in patients with IBD and colorectal tumors and aimed to clarify the utility of these fecal markers. Methods: In this study, 104 patients were analyzed, including 25 patients with ulcerative colitis (UC), 20 with Crohn's disease (CD), 48 with colorectal tumors, and 13 healthy controls (HC). Of the 48 patients with colorectal tumors, 14 had invasive cancer. We validated the utility of fecal Cp, Lf, and Hb levels by simultaneously measuring fecal markers in patients with IBD and colorectal tumors. Results: Fecal Cp and Lf had almost equivalent abilities in detecting clinical remission in patients with UC; however, fecal Cp was slightly superior to Lf. Regarding colorectal tumors, fecal Cp and Lf levels tended to be higher in patients with adenomas and colorectal cancer than in HCs. Although fecal Hb alone had the best sensitivity and specificity for detecting colorectal cancer, it had relatively low sensitivity for detecting advanced neoplasms and colorectal cancer. Conclusion: Fecal Cp and Lf can be used as almost equivalent biomarkers to assess the clinical activity in patients with UC. Fecal Hb is the most useful marker for screening colorectal cancer; however, adding fecal Cp and Lf may compensate for the low sensitivity of detecting for advanced colorectal tumors based on Hb alone.

Effectiveness and Persistency of Ustekinumab Treatment for Ulcerative Colitis: A Phoenix retrospective Cohort Study.

Background: Real-world data regarding ustekinumab (UST) for ulcerative colitis (UC) particularly in biologics-naïve patients is currently limited. This study aimed to elucidate the real-world effectiveness and safety of UST for UC. Methods: Overall, 150 patients with UC treated with UST from March 2020 to January 2023 were enrolled across 7 referral hospitals. To assess the clinical efficacy and persistence of UST, retrospective analyses were conducted from weeks 8 to 56. Predictive factors concerning the response and persistence of UST were examined through univariate and multivariate analyses. Results: Of the 150 patients, 125 received UST for remission induction, including 36% biologics-naïve. The response and remission rates were 72.8% and 56.0% at week 8 and 73.2% and 63.4% at week 56, respectively. Biologics-naïve patients represented higher response and remission rates at week 8 (84.4% and 73.3%) than those with biologics exposure (66.2% and 46.2%). Patients with prior antitumor necrosis factor (anti-TNF) and vedolizumab (VDZ) exposure had relatively lower response and remission rates (34.5% and 24.1%, respectively). The 1-year cumulative persistence rate was 84.0%. Multivariate analysis revealed that the chronic continuous type and prior anti-TNF and VDZ exposure were negative predictive factors for week 8 responsiveness. Clinical response at week 8 was a predictor of 1-year persistence. Adverse event incidence remained notably low at 6.4%. Conclusions: This study highlights the safety and effectiveness of UST as an induction and maintenance therapy for UC. Chronic continuous type and previous anti-TNF and VDZ exposure negatively contributed to short-term effectiveness, whereas short-term effectiveness provided good persistency.

Cytokine Profile in Predicting the Effectiveness of Advanced Therapy for Ulcerative Colitis: A Narrative Review.

Cytokine-targeted therapies have shown efficacy in treating patients with ulcerative colitis (UC), but responses to these advanced therapies can vary. This variability may be due to differences in cytokine profiles among patients with UC. While the etiology of UC is not fully understood, abnormalities of the cytokine profiles are deeply involved in its pathophysiology. Therefore, an approach focused on the cytokine profile of individual patients with UC is ideal. Recent studies have demonstrated that molecular analysis of cytokine profiles in UC can predict response to each advanced therapy. This narrative review summarizes the molecules involved in the efficacy of various advanced therapies for UC. Understanding these associations may be helpful in selecting optimal therapeutic agents.

Long-term effectiveness and safety of infliximab-biosimilar: A multicenter Phoenix retrospective cohort study.

BACKGROUND: Infliximab (IFX) effectively treats patients with inflammatory bowel disease (IBD). IFX-biosimilar (IFX-BS) has the same amino acid sequence as that of the IFX originator, and its increasing use is expected to reduce national healthcare costs. Long-term efficacy and safety of IFX-BS in patients with Crohn's disease (CD) and ulcerative colitis (UC) have not been completely investigated. METHODS: We conducted a retrospective, multicenter observational study of patients with IBD who received IFX-BS treatment at three hospitals between October 2016 and April 2022. Clinical data were collected from electronic medical records and evaluated for achieving clinical remission (CR) using Crohn's disease activity index (CDAI) and partial Mayo (pMayo) score, persistency of long-term IFX-BS administration, and clinical response rate in the bio-naïve and bio-failure groups. RESULTS: A total of 117 patients with IBD (90 CD and 27 UC) were included. The study findings indicated that both bio-naïve and bio-failure groups of patients with UC showed similar effectiveness of IFX-BS. The treatment persistence rate in patients with CD was significantly higher in the bio-naïve (P = 0.042) and switch (P = 0.010) groups than in the bio-failure group. In the former two groups, the treatment persistence rate was high at two years after administration (more than 80%). In patients with UC, the findings indicated higher treatment persistence rate in the switch group than in the bio-naïve group. Univariable and multivariable analyses for treatment persistence rate showed that the albumin level at the initial IFX-BS administration and groups (bio-naïve, bio-failure and switch) were effective factors for patients with CD. Adverse events were reported in 18 patients (15.4%). CONCLUSION: The present study demonstrates the long-term effectiveness and safety of IFX-BS. In addition to the favorable remission induction in the bio-naïve and bio-failure groups, we demonstrated remission maintenance and treatment persistence rates beyond two years. Albumin level and groups were associated with better treatment persistence in patients with CD.

Application of plasma alternative to serum for measuring leucine-rich α2-glycoprotein as a biomarker of inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic intestinal disorder characterized by recurrent flare-ups and remission. Leucine-rich α2-glycoprotein (LRG) has been developed as a new serum biomarker of disease activity in patients with IBD. However, there have been no reports on whether plasma LRG can be used as an alternative to serum LRG. Therefore, in this retrospective study, we evaluated the usefulness of plasma LRG compared to serum LRG. METHODS: We conducted a single-center retrospective observational study. A total of 108 IBD patients (ulcerative colitis [UC], 56; Crohn's disease [CD], 52) who received treatment at Sapporo Medical University Hospital between August 2020 and September 2021 were enrolled. Serum and plasma LRG levels were measured using the NANOPIA LRG kit. Disease activity was assessed using the Crohn's Disease Activity Index (CDAI) for CD and partial Mayo (pMayo) score for UC. Endoscopic activity was evaluated using the Mayo Endoscopic Subscore (MES) and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) in patients with UC and the Simple Endoscopic Score for Crohn's Disease (SES-CD) score in patients with CD. RESULTS: Serum LRG levels significantly correlated with plasma LRG levels (r = 0.990, p<0.0001). Plasma LRG levels were significantly associated with SES-CD (r = 0.992, p<0.0001), indicating that plasma LRG levels may predict endoscopic activity in CD. In UC patients, the cutoff values of plasma LRG for remission were 12.7 µg/mL for MES ≤1 and 10.0 µg/mL for UCEIS of = 0. CONCLUSION: The present study showed that plasma LRG levels correlate well with serum LRG levels. Therefore, plasma LRG can be clinically applied as a biomarker for assessing endoscopic disease activity in patients with IBD.

Immune-related colitis and pancreatitis treated with infliximab.

Patients with various cancers benefit from immune checkpoint inhibitors. However, immune checkpoint inhibitor-induced adverse events have also been reported, such as colitis. Prednisolone is the first-line treatment for immune-related adverse events, but second-line therapy for patients refractory to steroids has not been established. Furthermore, the inflammatory cytokine expression pattern in the intestinal mucosa of patients with steroid-refractory immune-related colitis remains unclear. We present the case of a 48-year-old man diagnosed with immune-related colitis and pancreatitis induced by pembrolizumab for advanced lung cancer. First, we administered 50 mg/day of prednisolone, and the patient's abdominal symptoms improved. However, the pancreatic enzyme levels did not return to normal. Furthermore, the patient's diarrhea worsened and hematochezia appeared at a 40 mg/day prednisolone dose. A mucosal cytokine analysis identified a low interleukin-10 messenger RNA level, which has been associated with a poor response to prednisolone. Thus, we administered 5 mg/kg of infliximab; the patient's diarrhea and hematochezia immediately improved, and the pancreatic enzyme levels returned to normal. Infliximab was administered three times every 2 weeks. After, the patient's colitis and pancreatitis did not recur. To our knowledge, this is the first report demonstrating the effectiveness of infliximab for immune-related colitis and pancreatitis.

An older patient with active ulcerative colitis and coronavirus disease 2019 (COVID-19) pneumonia successfully treated with the combination of anti-TNFα therapy and azathioprine.

A 77-year-old patient with ulcerative colitis (UC) was transferred to our department because of worsening bloody diarrhea and abdominal pain, which was consistent with a UC flare. Two days after admission, she complained of cough and high fever. The polymerase chain reaction (PCR) test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was positive, and a computed tomography showed pneumonia in the left lobe, consistent with coronavirus disease 2019 (COVID-19) pneumonia. However, frequent bloody diarrhea and abdominal pain due to the UC flare persisted; therefore, an additional immunosuppressive agent needed to be considered. We initiated infliximab biosimilar (IFX-BS), and her abdominal symptoms improved. However, they deteriorated after the second IFX-BS infusion. After confirming that the patient was negative for SARS-CoV-2 by PCR, we administered a combination of azathioprine and IFX-BS. The combination treatment improved her intestinal symptoms without worsening COVID-19 pneumonia. She has remained in remission for over a year since her discharge.

The association between antigenemia, histology with immunohistochemistry, and mucosal PCR in the diagnosis of ulcerative colitis with concomitant human cytomegalovirus infection.

BACKGROUND: Human cytomegalovirus (HCMV) colitis can be involved in active ulcerative colitis (UC) in patients refractory to steroid and immunosuppressive drugs. Histological examination with colonic biopsy specimens and antigenemia assays are the standard tests for diagnosing HCMV enterocolitis, and we have previously reported the usefulness of mucosal polymerase chain reaction (PCR) methods. However, the associations among histopathological tests, antigenemia assays, and mucosal PCR are unknown. METHODS: We retrospectively analyzed 82 UC patients who underwent mucosal biopsy from inflamed colonic tissues for histological evaluation and mucosal PCR to detect HCMV. We analyzed the relationships between the HCMV-DNA copy number in colonic mucosa and other HCMV tests. RESULTS: In total, 131 HCMV mucosal PCR tests from 82 UC patients were positive. The HCMV-DNA copy number was significantly higher in patients with positive immunohistochemistry (IHC) (p < 0.01) and was correlated with the number of positive cells for the antigenemia (C7-HRP, p < 0.01; C10/11, p < 0.01). Receiver operating characteristic curve analysis confirmed 1300 copies/µg of HCMV-DNA as the best diagnostic cut-off value to predict positive results of antigenemia (area under the curve = 0.80, 95% CI 0.68-0.93). HCMV-DNA copy number also correlated with the total UCEIS score (p = 0.013) and the bleeding score (p = 0.014). For each individual patient, a positive correlation between the change in total UCEIS score and HCMV-DNA copy number was observed (p = 0.040). CONCLUSION: The antigenemia assay and histopathological test with IHC were significantly associated with the HCMV-DNA copy number in colonic tissues. Moreover, endoscopic examination with the UCEIS can help diagnose the HCMV colitis in UC patients.

[Report on a new remote collaborative medical care system -construction and operation of a remote collaborative medical care network for inflammatory bowel disease using information and communication technology in Hokkaido].

Inflammatory bowel disease (IBD) comprises 2 major types-ulcerative colitis (UC) and Crohn's disease (CD). A remote collaborative medical care fee has been established for patients with suspected intractable diseases since 2020. Remote collaborative medical care is a type of telemedicine wherein a hospital specialist for intractable diseases, the patient, and an attending physician at a community hospital communicate via video calls. In IBD cases, however, treating patients who have already been diagnosed with severe or intractable diseases is difficult. As a part of the Hokkaido Intractable Disease Medical Care System Development Project, we have started providing free remote collaborative medical care services for all IBD patients, including those with a confirmed diagnosis and attending regional hospitals. We set up the telemedicine system using Microsoft365, a commercial cloud, and Nextcloud, a PaaS, to ensure robust security and enable rapid and massive sharing of medical details by information and communication technology. Since April 2021, we have examined 27 patients (36 times). Among these patients, 5 patients from regional hospitals were undiagnosed (1 patient of suspected CD, 3 patients of suspected IBD unclassified (IBD-U), and 1 patient of undiagnosed enteritis). Twenty-two patients from regional hospitals had a confirmed diagnosis (17 UC and 5 CD patients). Eight patients required a second time remote collaborative medical care, and 1 patient required a third time remote collaborative medical care. There was no equipment failure such as communication failure or system trouble, and all patients could be examined smoothly. The maintenance cost of the telemedicine system was 2500yen/month per hospital. Among all cases receiving remote collaborative medical care, 86% were consultations for refractory or severe active cases with a confirmed diagnosis of IBD. At present, the remote collaborative medical care fee for diagnosed patients is not permitted. Since remote collaborative medical care has the potential to correct regional disparities in medical standards, there is an urgent need to review the criteria for remote collaborative medical care fees.

Extensive mucosal sloughing of the small intestine and colon in a patient with severe COVID-19.

Patients with coronavirus disease 2019 (COVID-19) primarily cause respiratory symptoms. However, gastrointestinal (GI) symptoms can also occur. The endoscopic characteristics of the GI tract in COVID-19 patients remain unclear. We herein report a 62-year-old male with severe COVID-19 who needed multidisciplinary treatment, including extracorporeal membrane oxygenation (ECMO). Despite the improvement in his respiratory status, GI bleeding developed. Capsule endoscopy and colonoscopy revealed extensive mucosal sloughing in the lower intestinal tract. Additionally, we performed a comprehensive analysis of the mRNA expression levels of various proinflammatory cytokines in the intestinal mucosal tissues. The results suggested a significant elevation of IL-6, which could be involved in the pathophysiology of the GI involvement in COVID-19. Further investigation with more clinical data, including endoscopic findings and molecular analyses, will contribute to a comprehensive understanding of COVID-19-associated GI injury.

Mediterranean fever gene-associated enterocolitis in an elderly Japanese woman.

An 86-year-old woman was admitted to our hospital with anemia. She had never experienced symptoms of serositis. Colonoscopy revealed colitis with erosions and a friable mucosa. First, she was diagnosed with unclassified inflammatory bowel disease (IBD-U). We suspected familial Mediterranean fever as a differential diagnosis of IBD-U, and MEFV gene analysis showed heterozygosity for Exon2 R202Q. The patient was treated with colchicine 0.5 mg. After 4 months, a follow-up colonoscopy showed remarkable improvement of the mucosal inflammation throughout the entire colon. MEFV gene-associated enterocolitis responding to colchicine may be observed in patients with IBD-U and elucidating the role of MEFV gene mutations in intestinal inflammation is a future challenge.

Gastrointestinal involvement in a patient with familial Mediterranean fever mimicking Crohn's disease: a case report.

Familial Mediterranean fever (FMF) in gastrointestinal involvement has been considered rare, but resent reports suggest that FMF causes enterocolitis which is similar endoscopic findings to inflammatory bowel disease. The clinical characteristics and endoscopic findings of FMF with enterocolitis remain unclear. Here, we report a case of an FMF patient who had enterocolitis with stricture of the terminal ileum whose endoscopic and clinical features mimicked Crohn's disease. A 23-year-old man who was diagnosed with FMF 10 years ago presented with abdominal pain and diarrhea. Colonoscopy showed terminal ileitis and aphthous colitis; however, these findings, including the histopathology, did not confirm Crohn's disease. Therefore, we diagnosed FMF with enterocolitis and administered anti-interleukin-1ß monoclonal antibody (canakinumab). The patient's symptoms improved with treatment, but after 1 year, lower abdominal pain recurred. Colonoscopy revealed a stricture of the terminal ileum. Endoscopic balloon dilation relieved his symptoms. At present, he has been followed up without surgical treatment by endoscopic balloon dilation every 6 month. Clinicians should be aware that FMF accompanied with enterocolitis may resemble Crohn's disease.

Successful hemostasis of bleeding gastric inflammatory fibroid polyp by endoscopic treatment in a patient with severe COVID-19.

The coronavirus disease-2019 (COVID-19) has rapidly become a pandemic, resulting in a global suspension of non-emergency medical procedures such as screening endoscopic examinations. There have been several reports of COVID-19 patients presenting with gastrointestinal symptoms such as diarrhea and vomiting. In this report, we present a case of successful hemostasis of bleeding gastric inflammatory fibroid polyp by endoscopic treatment in a patient with severe COVID-19. The case was under mechanical ventilation with extracorporeal membrane oxygenation (ECMO), and the airway was on a closed circuit. This indicates that COVID-19 is associated with not only lung injury but also intestinal damage, and that proper protective protocols are essential in guaranteeing the best outcomes for patients and clinical professionals during this pandemic.

The characteristics of gastrointestinal symptoms in patients with severe COVID-19: a systematic review and meta-analysis.

Although primarily a respiratory illness, several studies have shown that COVID-19 causes elevation of liver enzymes and various gastrointestinal (GI) symptoms. The aim of this study was to undertake a systematic review and meta-analysis to determine whether the presence of gastrointestinal (GI) symptoms contributed toward COVID-19 severity, and identify the GI symptoms characteristic of severe COVID-19. We conducted a literature search of PubMed from December 1, 2019, to June 30, 2020, and identified all reports with GI symptoms reported. A meta-analysis comparing the severity of COVID-19 with the presence of liver enzyme elevation and GI symptoms was performed using RevMan version 5.4. Pooled data from 15,305 unique reverse transcriptase-polymerase chain reaction positive COVID-19 patients from 44 studies were analyzed. We found that the severe COVID-19 patients significantly had abdominal pain compared to the non-severe COVID-19 patients (OR = 2.70, 95% CI 1.17-6.27, Z = 2.32, p = 0.02, I2 = 0%) by analyzed 609 patients of 4 studies who reported both abdominal pain and COVID-19 severity. However, there was no significant difference in the incidence of diarrhea, nausea, or vomiting between the two groups. Thus, this systematic review and meta-analysis demonstrated that abdominal pain could be characteristic of severe COVID-19 infections. Compared with other viral infections that primarily infect the respiratory system, patients with COVID-19 have a slightly lower frequency of diarrheal symptoms with abdominal pain. However, to confirm this, further studies with COVID-19 patients across various countries and ethnicities are required.

Artificial intelligence-assisted endoscopy changes the definition of mucosal healing in ulcerative colitis.

The relevance of endoscopic monitoring of ulcerative colitis (UC) has been translated into the new concept of "mucosal healing (MH)" as the therapeutic goal to achieve because a large amount of scientific data have revealed the favorable prognostic value of a healed mucosa in determining the clinical outcome of UC. Recent interest in MH has skewed toward not only endoscopic remission but also histological improvement (so called histological MH). However, we should recognize that there have been no prospectively validated endoscopic scoring systems of UC activity in previous clinical trials. Artificial intelligence (AI)-assisted endoscopy has been developed for gastrointestinal cancer surveillance. Recently, several AI-assisted endoscopic systems have been developed for assessment of MH in UC. In the future, the development of a new endoscopic scoring system based on AI might standardize the definition of MH. Therefore, "The road to an exact definition of MH in the treatment of UC has begun only now".

Double small bowel cancers leading to the diagnosis of Lynch syndrome with germline MSH6 mutation in an elderly patient.

A female patient in her 80s was referred to our hospital because of an ileal tumor identified by capsule endoscopy. FDG-PET suggested double intestinal tumors not only in the ileum but also in the jejunum. The patient has cancer past history including sigmoid colon, rectum, and endometrium, and also had cancer family history fulfilling the revised Amsterdam criteria. Double balloon enteroscopy disclosed two ulcerated tumors in the jejunum and the ileum. Biopsy was diagnosed as adenocarcinoma pathologically, and microsatellite instability-high (MSI-H) genetically. Surgical resection was performed, and the jejunal and the ileal tumors were tubular (T2N0M0) and mucinous adenocarcinoma (T4N0M0), respectively. Germline mutation analysis revealed a pathogenic splice-site mutation in MSH6.