The evolving understanding of histology as an endpoint in ulcerative colitis.

A therapeutic goal for patients with ulcerative colitis (UC) is deep remission including clinical remission and mucosal healing. Mucosal healing was previously defined by endoscopic appearance, but recent studies demonstrate that histological improvements can minimize the risks of experiencing clinical relapse after achieving endoscopic remission, and there is growing interest in the value and feasibility of histological targets of treatment in inflammatory bowel disease, and specifically UC. In this review article, we identify remaining challenges and discuss an evolving role of histology in the management of UC.

Measurement of the intracellular active metabolites of thiopurine drugs to evaluate the enzymatic activity of nudix hydrolase 15 in human blood samples.

Thiopurine is metabolized to 6-thio-(deoxy) guanosine triphosphate (6-thio-(d) GTP), which is then incorporated into DNA or RNA and causes cytotoxicity. Nudix hydrolase 15 (NUDT15) reduces the cytotoxic effects of thiopurine by converting 6-thio-(d) GTP to 6-thio-(d) guanosine monophosphate (6-thio-(d) GMP). NUDT15 polymorphisms like the Arg139Cys variant are strongly linked to thiopurine-induced severe leukocytopenia and alopecia. Therefore, measurement of NUDT15 enzymatic activity in individual patients can help predict thiopurine tolerability and adjust the dosage. We aimed to develop a quantitative assay for NUDT15 enzymatic activity in human blood samples. Blood samples were collected from donors whose NUDT15 genetic status was determined. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to assess the 6-thio-GTP metabolic activity in cell extracts. Because 6-thio-guanosine diphosphate (6-thio-GDP) and 6-thio-GMP were generated upon incubation of 6-thio-GTP with human blood cell extracts, the method detecting 6-thio-GTP, 6-thio-GDP, and 6-thio-GMP was validated. All three metabolites were linearly detected, and the lower limit of quantification (LLOQ) of 6-thio-GTP, 6-thio-GDP, and 6-thio-GMP were 5 µM, 1 µM, and 2 µM, respectively. Matrix effects of human blood cell extracts to detect 6-thio-GTP, 6-thio-GDP, and 6-thio-GMP were 99.0 %, 100.5 %, and 101.4 %, respectively, relative to the signals in the absence of blood cell extracts. The accuracy and precision of the method and the stability of the samples were also assessed. Using this established method, the genotype-dependent differences in NUDT15 activities were successfully determined using cell extracts derived from human blood cells with NUDT15 wild-type (WT) or Arg139Cys variant and 6-thio-GTP (100 µM) as a substrate (18.1, 14.9, and 6.43 µM/h/106 cells for WT, Arg139Cys heterozygous, and homozygous variant, respectively). We developed a method for quantifying intracellular NUDT15 activity in peripheral blood mononuclear cells (PBMCs), which we defined as the conversion of 6-thio-GTP to 6-thio-GMP. Although PBMCs preparation takes some time, its reproducibility in experiments makes it a promising candidate for clinical application. This method can tell the difference between WT and Arg139Cys homozygous blood samples. Even in patients with WT NUDT15, WT samples showed variations in NUDT15 activity, which may correlate with variations in thiopurine dosage.

Dual-Targeted Therapy with Upadacitinib and Ustekinumab in Medically Complex Crohn's Disease.

BACKGROUND AND AIMS: Ongoing efforts to break the therapeutic ceiling in inflammatory bowel disease include combination therapy approaches. Dual-targeted therapy (DTT) has been reported in case reports and small case series. This report describes our experience with ustekinumab (UST) and upadacitinib (UPA) as DTT in patients with Crohn's disease (CD). METHODS: In this retrospective, observational study, we reviewed medical records of patients with CD treated with combined UST and UPA between April 2021 and July 2022. Clinical remission was defined as Harvey-Bradshaw Index (HBI) ≤ 4, and clinical response was defined as decrease in HBI ≥ 3 or physician's assessment of clinical response. RESULTS: We identified 10 CD patients treated with UST/UPA, with median follow-up period of 10 months (interquartile range (IQR) 7.3-12). Median age was 35.5 years (IQR 28.3-43.8) and median number of prior biologic treatment exposures was 4 (IQR 4-5). Indications for UST/UPA were active CD (n = 6), extraintestinal manifestations (EIM) (n = 2), and both active CD and EIM (n = 2). Five of six patients with active CD achieved clinical remission with UST/UPA. Two patients with active EIM (joint pain) achieved resolution of their symptoms. One patient exhibited improvement in both conditions. Three patients developed mild respiratory symptoms and one experienced bowel obstruction. Two patients developed nausea resulting in de-escalation of treatment interval or discontinuation altogether. CONCLUSION: Based on our case series, combination therapy with UST and UPA may be effective and appears safe in refractory Crohn's disease and for patients with co-existing extraintestinal manifestations.

Milan Ultrasound Criteria Predict Relapse of Ulcerative Colitis in Remission.

Introduction: Bowel ultrasound is a noninvasive alternative to endoscopy for assessing the disease activity of ulcerative colitis; however, it is unclear whether bowel ultrasound can predict subsequent relapse from remission. Materials and Methods: A retrospective cohort study enrolled patients with ulcerative colitis who underwent bowel ultrasound between July 2018 and July 2021 during clinical remission (patient-reported outcome-2 ≤1 and no rectal bleeding) for at least 3 months and were followed up for 1 year. Ultrasonographic findings (bowel wall thickness, bowel wall flow, bowel wall stratification, and enlarged lymph nodes), Milan ultrasound criteria, Mayo endoscopic subscore, C-reactive protein, and fecal calprotectin levels and their association with subsequent clinical relapse were assessed. Relapse was defined as rectal bleeding score ≥1, stool frequency score ≥2, or treatment intensification for symptoms. Results: 31% of the patients (18/58) relapsed within 1 year. No single ultrasonographic finding predicted relapse, whereas Milan ultrasound criteria >6.2 (p = 0.019), Mayo endoscopic subscore ≥1 (p = 0.013), and fecal calprotectin ≥250 µg/g (p = 0.040) were associated with a shorter time to relapse in the log-rank test. Milan ultrasound criteria >6.2 (hazard ratio 3.22; 95% confidence interval 1.14-9.08, p = 0.027) and Mayo endoscopic subscore ≥1 (hazard ratio 8.70; 95% confidence interval 1.11-68.1, p = 0.039) showed a higher risk of relapse according to a Cox proportional hazards model. Conclusion: Bowel ultrasound can predict subsequent clinical relapse from remission in patients with ulcerative colitis using the Milan ultrasound criteria.

At-home Disease Monitoring by Patient-performed Intestinal Ultrasound in Severe Ulcerative Colitis.

We describe the first reported case of a nonmedically trained patient using a handheld ultrasound device to monitor his ulcerative colitis in real time at home during induction therapy for severe colitis.

Optimal Use of Serum Leucine-Rich Alpha-2 Glycoprotein as a Biomarker for Small Bowel Lesions of Crohn's Disease.

Introduction: A large proportion of small bowel lesions in Crohn's disease (CD) may exist beyond the reach of ileocolonoscopy and there is no gold standard imaging modality to screen them, suggesting the need for optimal biomarkers. We aimed to compare the usefulness of C-reactive protein (CRP), faecal calprotectin (FC), and leucine-rich alpha-2 glycoprotein (LRG) in determining small bowel lesions of CD. Methods: This was a cross-sectional observational study. CRP, FC, and LRG were prospectively measured in patients with quiescent CD who underwent imaging examinations (capsule or balloon-assisted endoscopy, magnetic resonance enterography, or intestinal ultrasound) selected by the physician in clinical practice. Mucosal healing (MH) of the small bowel was defined as a lack of ulcers. Patients with a CD activity index >150 and active colonic lesions were excluded. Results: A total of 65 patients (27, MH; 38, small bowel inflammation) were analysed. The area under the curve (AUC) of CRP, FC, and LRG was 0.74 (95% confidence interval: 0.61-0.87), 0.69 (0.52-0.81), and 0.77 (0.59-0.85), respectively. The AUC of FC and LRG in a subgroup of 61 patients with CRP <3 mg/L (26, MH; 32, small bowel inflammation) was 0.68 (0.50-0.81) and 0.74 (0.54-0.84), respectively. The cut-off of 16 µg/mL of LRG showed the highest positive predictive value of 1.00 with specificity of 1.00, while negative predictive value was highest (0.71) with sensitivity of 0.89 at the cut-off of 9 µg/mL. Conclusion: LRG can accurately detect and/or exclude the small bowel lesions with two cut-off values.

Reducing Health Anxiety in Patients With Inflammatory Bowel Disease Using Video Testimonials: Pilot Assessment of a Video Intervention.

BACKGROUND: Health anxiety has many damaging effects on patients with chronic illness. Physicians are often unable to alleviate concerns related to living with a disease that has an impact on daily life, and unregulated websites can overrepresent extreme anxiety-inducing outcomes. Educational clinician video interventions have shown some success as an acute anxiolytic in health settings. However, little research has evaluated if peer-based video interventions would be a feasible alternative or improvement. OBJECTIVE: This pilot study assesses the efficacy of anxiety reduction for patients with Crohn disease (CD) and those with ulcerative colitis (UC) by showing patient testimonial videos during hospital visits. It investigates the degree to which patient testimonials can affect state anxiety, and whether patients are comfortable enough with the technology to share their stories. METHODS: Patients with CD (n=51) and those with UC (n=49) were shown testimonial videos of patients with CD during their physician consultations at Kitasato University Kitasato Institute Hospital in Japan. The video testimonials were collected from Dipex Japan, the Japan branch of an international organization specializing in understanding patient experiences. Patients completed a Visual Analogue Scale for Anxiety before and after viewing the videos, a Hospital Anxiety and Depression Scale (HADS) survey before the videos, and satisfaction surveys. Patients receiving infusion therapy participated in the study while receiving treatment to minimize hospital workflow disruption. RESULTS: Anxiety reduction, on the Visual Analog Scale for Anxiety, was significant in the entire cohort both when viewed as an ordinal variable (P=.003, t98=1086.5) and as a continuous variable (P=.01, t94=-2.54, 90% CI -3.47 to -0.72). Eighty percent (n=15) of patients with high HADS Anxiety (HADS-A) scores and 71% (n=24) of patients with high starting state anxiety experienced reduced anxiety after watching testimonials. Patients with high state anxiety but low HADS-A scores experienced anxiety reduction (69%, n=16). Forty-two percent (n=100) of patients responded that they would share their stories for future users. When patients with UC received testimonials from patients with CD, 71% (n=49) of patients reported that they were relevant despite differences in condition. CONCLUSIONS: Our pilot results suggest that patient testimonial videos can reduce illness-related state anxiety for patients with CD and those with UC, especially in those with higher baseline state anxiety. The success of this study in reducing anxiety and achieving patient involvement suggests that video interventions for reducing anxiety might be a low-cost intervention that could scale to any number of hospitals, suggesting that technology can help scale up efforts to record and share patient testimonials. Future work can establish whether patient testimonials can be helpful in other contexts, such as before major surgeries or when a family member receives a difficult diagnosis.

Medically Refractory Lymphocytic Colitis Successfully Treated With Upadacitinib.

Lymphocytic colitis is a microscopic colitis characterized endoscopically by nearly normal-appearing colonic mucosa and histology demonstrating intraepithelial lymphocytosis. Microscopic colitis that is refractory to conventional therapies, including budesonide, is rare but challenging and with scarce evidence. Upadacitinib is a novel Janus kinase 1 selective inhibitor approved by the US Food and Drug Administration for atopic dermatitis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and moderately to severely active ulcerative colitis. We present the first case of lymphocytic colitis refractory to conventional and immunosuppressive therapies, which responded promptly to upadacitinib.

Evidence-Based Approach to the Discontinuation of Immunomodulators or Biologics in Inflammatory Bowel Disease.

BACKGROUND: Biologics and immunomodulators are key drugs in the long-term treatment of inflammatory bowel diseases, while they may negatively impact patients' quality of life due to concerns of adverse events, need for frequent hospital visits, and medical expenses. The basic concept of drug withdrawal should be based on the risk of relapse and the efficacy of re-treatment. Considering a number of patients may relapse even if treatment is continued, the disadvantage of discontinuation should be recognized not by all relapse after discontinuation, but by the increase in relapse. SUMMARY: Discontinuation of immunomodulator monotherapy is associated with an increased risk of relapse. However, prolonged remission might be an indication of withdrawal, concerning the long-term adverse effect including lymphoma and nonmelanoma skin cancers. When considering discontinuation from combination therapy of anti-tumor necrosis factor (TNF) agents with immunomodulators, therapeutic drug monitoring may be useful to understand the pharmacokinetic effect. However, recent randomized controlled trials, as well as large-scale observational studies, demonstrated that discontinuation of anti-TNF agents, but not of immunomodulators, resulted in a significantly higher risk of relapse even in deep remission. Therefore, discontinuation of anti-TNF agents should be considered with caution and close monitoring combined with fecal calprotectin may be necessary. On the other hand, evidence of not only short-term relapse rate but of the true long-term influence on the patient's quality of life should be clarified by a multidimensional approach. KEY MESSAGES: Discontinuation of treatment should be implemented based on shared decision-making with careful interpretation of evidence and the condition.

De-escalation of Therapy in Patients with Quiescent Inflammatory Bowel Disease.

Inflammatory bowel disease is a chronic disease of unknown origin that requires long-term treatment. The optical duration of maintenance treatment once remission has been achieved remains unclear. When discussing a de-escalation strategy, not only the likelihood of relapse but also, the outcome of retreatment for relapse after de-escalation should be considered. Previous evidence has demonstrated controversial results for risk factors for relapse after de-escalation due to the various definitions of remission and relapse. In fact, endoscopic or histologic remission has been suggested as a treatment target; however, it might not always be indicative of a successful drug withdrawal. For better risk stratification of relapse after de-escalation, it may be necessary to evaluate both the current and previous treatments. Following de-escalation, biomarkers should be closely monitored. In addition to the risk of relapse, a comprehensive understanding of the overall outcome, such as the long-term safety, patient quality of life, and impact on healthcare costs, is necessary. Therefore, a shared decision-making with patients on a case-by-case basis is imperative.

Usefulness of colestimide for diarrhea in postoperative Crohn's disease.

Background and Aim: Crohn's disease (CD) often causes intractable diarrhea after intestinal resection. Anion exchange resins have been reported to be effective in patients with bile acid diarrhea after distal ileectomy; furthermore, bile acid metabolism has been implicated in the pathogenesis of CD. Therefore, we aimed to examine the effectiveness of colestimide in the management of postoperative CD, and to compare its impact between patients with and those without ileocecal resection. Methods: Postoperative CD patients prescribed colestimide for diarrhea between April 2017 and December 2020 were retrospectively evaluated for changes in the total Crohn's disease activity index (CDAI), each CDAI component including diarrhea frequency/week, albumin, and C-reactive protein (CRP) was evaluated before and after the administration of colestimide. Furthermore, comprehensive patient and physician assessments were reviewed from medical records during the first outpatient visit as a global clinical judgment after the initiation of colestimide therapy. Results: A total of 24 patients were included, of whom 17 had a previous history of ileocecal resection. Significant improvement was noted in CDAI and diarrhea frequency only in the ileocecal resection group (CDAI: 114.5 ± 52.7 and 95.4 ± 34.8, P < 0.05; diarrhea frequency/week 23.8 ± 14.1 and 15.4 ± 11.2, P < 0.05, respectively). There was no significant improvement in other CDAI components, albumin level, or CRP level in either group. In the global clinical judgment, 13 and 4 patients in the ileocecal and non-ileocecal resection groups, respectively, were judged as "effective," with an overall efficacy rate of 70.8%. Conclusion: Colestimide is effective for diarrhea in patients with postoperative CD, especially after ileocecal resection.

Early improvement in bowel wall thickness on transperineal ultrasonography predicts treatment success in active ulcerative colitis.

BACKGROUND: Bowel ultrasonography is a non-invasive imaging tool that can repeatedly monitor ulcerative colitis (UC) activity. AIM: This study aimed to determine whether early transabdominal or transperineal ultrasonography changes can predict subsequent clinical response to induction therapy in patients with UC. METHODS: This single-centre prospective study explored ultrasonographic predictors for clinical remission (patient-reported outcome-2 ≤ 1 with no rectal bleeding subscore) at week 8 in patients with active UC who underwent induction therapy, in comparison with faecal calprotectin and C-reactive protein (measured at baseline, week 1 and week 8). Predictive factors were assessed using multivariable regression models and receiver-operating-characteristic curve analysis. RESULTS: A total of 100 patients were analysed, of which 54 achieved remission at week 8. Baseline biomarker and ultrasonographic-parameter values were not predictive of remission. Contrastingly, change from baseline to week 1 in rectal bowel wall thickness measured using transperineal ultrasonography was an independent predictor of remission by week 8 (adjusted odds ratio is associated with a 1-mm decrease: 1.90 [95% confidence interval, 1.22-2.95]). In a subgroup analysis of the patients who did not achieve remission in 1 week, the predictive value of change in rectal bowel wall thickness remained high (AUC = 0.77 [95% confidence interval, 0.61-0.88]). CONCLUSION: Improvement in rectal bowel wall thickness measured using transperineal ultrasonography at week 1 predicts treatment success and potentially facilitates decision making during the early course of induction therapy in UC.

Residual Short-Segment Distal Inflammation Has No Significant Impact on the Major Relapse of Extensive Ulcerative Colitis.

BACKGROUND: Mucosal healing is a treatment target for patients with ulcerative colitis. However, the relevance of proactive treatment for residual inflammation limited to the distal colon is unclear. MATERIALS AND METHODS: Patients with ulcerative colitis who had extensive colitis in clinical remission and underwent colonoscopy were retrospectively enrolled and followed up for 2 years. Patients with complete endoscopic remission (CER; Mayo endoscopic subscore [MES] of 0) and those with short-segment distal inflammation (SS; active inflammation only in the sigmoid colon and/or rectum with a proximal MES of 0) were compared for the incidence of minor (only symptomatic) and major (need for induction treatments or hospitalization) relapses. RESULTS: A total of 91 patients with CER and 54 patients with SS were identified and 63 relapses (47 minor and 16 major) were analyzed. Univariate analysis showed that minor relapses were significantly more frequent in the SS group than in the CER group (hazard ratio [HR], 2.22; 95% confidence interval [CI], 1.25-3.97), but major relapses were not more frequent in the SS group than in the CER group (HR, 1.78; 95% CI, 0.65-4.83). Multivariable analysis showed that SS was the only risk factor significantly associated with minor relapse (HR, 2.38; 95% CI, 1.31-4.36). When the SS group was stratified by MES of 1 vs 2/3, minor relapses were significantly more frequent in the subgroup with MES of 2/3 than in the CER group, whereas the incidence of major relapse remained similar. CONCLUSIONS: Residual short-segment distal inflammation is not a risk factor for major relapses as long as endoscopic remission is achieved in the proximal colon. Therefore, reactive but not proactive treatment may be appropriate for such lesions.

Accuracy of Ultrasound for Evaluation of Colorectal Segments in Patients With Inflammatory Bowel Diseases: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: The accuracy of ultrasound for evaluation of individual colorectal segments in patients with inflammatory bowel diseases (IBD) has not been evaluated in a systematic review. We evaluated the diagnostic accuracy of ultrasound in different colorectal segments of patients with IBD. METHODS: We searched publication databases from inception through March 2019 for studies that assessed the accuracy of ultrasound in detection of inflammation in right, transverse, and left colon and in rectum in patients with IBD, using findings from colonoscopy as the reference standard. Subgroup analyses were performed including IBD type, patient age, body mass index, and study design. The risk of bias was assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 tool. RESULTS: Nineteen studies (1101 patients) were included in the qualitative synthesis. After we assessed the risk of bias, 7 studies (comprising 84 patients with Crohn's disease and 420 patients with ulcerative colitis) were included in the meta-analysis. Bowel wall thickness ≥ 3 mm identified colorectal segments with inflammation with 86.4% pooled sensitivity (95% CI, 76.1%-92.7%) and 88.3% pooled specificity (95% CI, 58.1%-97.6%). In rectum only, bowel wall thickness ≥ 3 mm identified inflammation with 74.5% sensitivity (95% CI, 53.0%-88.3%) and 69.5% specificity (95% CI, 33.6%-91.1%). Diagnostic accuracy was comparable among subgroups. Increased bowel wall flow and loss of stratification had higher true-positive odds ratios. CONCLUSIONS: Based on meta-analysis of patient-level data, ultrasound has higher diagnostic accuracy for detecting inflammation in colon than rectum in patients with IBD. Studies are needed to increase the accuracy of ultrasound detection of inflammation in rectum.

Determining the usefulness of Capsule Scoring of Ulcerative Colitis in predicting relapse of inactive ulcerative colitis.

BACKGROUND AND AIM: The usefulness of second-generation colon capsule endoscopy (CCE2) in ulcerative colitis (UC), especially in clinically inactive patients, has been reported. Capsule Scoring of Ulcerative Colitis (CSUC) was developed as a severity index for UC. We aimed to determine whether CSUC is useful for predicting relapse during clinical remission. METHODS: Forty-one UC patients in clinical remission who underwent CCE2 were prospectively registered from April 2016 to August 2019. Patients' CSUC score was obtained; those with subsequent relapse were followed up retrospectively. The correlation of CSUC with white blood cell count, platelet count, albumin, C-reactive protein, fecal calprotectin and fecal lactoferrin levels, and fecal immunochemical test results was evaluated; their predictive values for future relapse were compared. RESULTS: The correlations of CSUC with white blood cell, platelet, albumin, C-reactive protein, fecal calprotectin, fecal immunochemical test, and fecal lactoferrin values were rs  = 0.13, 0.27, -0.25, 0.15, 0.50, 0.43, and 0.50, respectively. CSUC was higher in 12 patients who relapsed within 1 year than in 29 patients who remained in clinical remission (2.83 ± 1.95 vs 0.72 ± 1.00, P < 0.01). Receiver operator characteristic curve analysis showed that CSUC ≥ 1 was a predictor of relapse (area under the curve of 0.82, sensitivity of 83.3%, specificity of 58.6%) and maybe superior to fecal biomarkers. In the univariate analysis, patients with CSUC of 0 had a lower relapse rate than those with CSUC of ≧ 1 (P = 0.03, log-rank test). After analyzing patients who underwent CCE2 within 6 months after the successful induction treatment, results showed that those with CSUC of ≤ 1 remained in clinical remission for a year. CONCLUSION: CSUC predicts relapse within 1 year in UC patients in clinical remission, especially when used 6 months after induction treatment.

Hyperammonemia with impaired consciousness caused by continuous 5-fluorouracil infusion for colorectal cancer: A case report.

A 66-year-old woman was diagnosed with stage IVb sigmoid colon cancer. Modified FOLFOX-6 (mFOLFOX-6; levofolinate‒fluorouracil‒oxaliplatin) plus panitumumab was selected as the chemotherapeutic regimen, but she was administered a regimen without oxaliplatin (L-OHP) or bolus 5-fluorouracil (5-FU) because of her general condition and concern about adverse effects. The patient had impaired consciousness on day 3 of chemotherapy. Computed tomography (CT) and magnetic resonance imaging (MRI) of the brain showed no findings of hemorrhage, infarction, brain metastasis, and leukoencephalopathy. Except for high blood ammonia concentration (353 µg/dL), there were no other findings that could have caused her condition. Impaired consciousness due to hyperammonemia was diagnosed. We started an intravenous drip supplemented with branched chain amino acids for liver protection. Approximately 6 hours later, blood ammonia level improved to 88 µg/dL, which approached the reference value. Consciousness level improved over time, reaching a level of alertness on day 5 after starting chemotherapy. 5-FU was suspected to be the cause of impaired consciousness due to hyperammonemia, but the exact cause could not be identified because most of the previously reported cases were given L-OHP, bolus 5-FU, and other concomitant medications. In this case, since there were no other concomitant medications, it is highly probable that continuous infusion of 5-FU alone caused impaired consciousness due to hyperammonemia. This is an important case that indicates the need to monitor carefully for the occurrence of hyperammonemia when 5-FU is administered continuously; it also proposes future issues for investigation.