Epithelial Nlrp10 inflammasome mediates protection against intestinal autoinflammation.

Unlike other nucleotide oligomerization domain-like receptors, Nlrp10 lacks a canonical leucine-rich repeat domain, suggesting that it is incapable of signal sensing and inflammasome formation. Here we show that mouse Nlrp10 is expressed in distal colonic intestinal epithelial cells (IECs) and modulated by the intestinal microbiome. In vitro, Nlrp10 forms an Apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC)-dependent, m-3M3FBS-activated, polyinosinic:polycytidylic acid-modulated inflammasome driving interleukin-1ß and interleukin-18 secretion. In vivo, Nlrp10 signaling is dispensable during steady state but becomes functional during autoinflammation in antagonizing mucosal damage. Importantly, whole-body or conditional IEC Nlrp10 depletion leads to reduced IEC caspase-1 activation, coupled with enhanced susceptibility to dextran sodium sulfate-induced colitis, mediated by altered inflammatory and healing programs. Collectively, understanding Nlrp10 inflammasome-dependent and independent activity, regulation and possible human relevance might facilitate the development of new innate immune anti-inflammatory interventions.

Development of antifibrotic therapy for stricturing Crohn's disease: lessons from randomized trials in other fibrotic diseases.

Intestinal fibrosis is considered an inevitable complication of Crohn's disease (CD) that results in symptoms of obstruction and stricture formation. Endoscopic or surgical treatment is required to treat the majority of patients. Progress in the management of stricturing CD is hampered by the lack of effective antifibrotic therapy; however, this situation is likely to change because of recent advances in other fibrotic diseases of the lung, liver, and skin. In this review, we summarize data from randomized controlled trials (RCTs) of antifibrotic therapies in these conditions. Multiple compounds have been tested for antifibrotic effects in other organs. According to their mechanisms, they were categorized into growth factor modulators, inflammation modulators, 5-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, intracellular enzymes and kinases, renin-angiotensin system (RAS) modulators, and others. From our review of the results from the clinical trials and discussion of their implications in the gastrointestinal tract, we have identified several molecular candidates that could serve as potential therapies for intestinal fibrosis in CD.

Upadacitinib Induction and Maintenance Therapy for Crohn's Disease.

BACKGROUND: Upadacitinib, an oral selective Janus kinase (JAK) inhibitor, is under investigation for the treatment of Crohn's disease. METHODS: In two phase 3 induction trials (U-EXCEL and U-EXCEED), we randomly assigned patients with moderate-to-severe Crohn's disease to receive 45 mg of upadacitinib or placebo (2:1 ratio) once daily for 12 weeks. Patients who had a clinical response to upadacitinib induction therapy were randomly assigned in the U-ENDURE maintenance trial to receive 15 mg of upadacitinib, 30 mg of upadacitinib, or placebo (1:1:1 ratio) once daily for 52 weeks. The primary end points for induction (week 12) and maintenance (week 52) were clinical remission (defined as a Crohn's Disease Activity Index score of <150 [range, 0 to 600, with higher scores indicating more severe disease activity]) and endoscopic response (defined as a decrease in the Simple Endoscopic Score for Crohn's Disease [SES-CD; range, 0 to 56, with higher scores indicating more severe disease] of >50% from baseline of the induction trial [or for patients with an SES-CD of 4 at baseline, a decrease of ≥2 points from baseline]). RESULTS: A total of 526 patients underwent randomization in U-EXCEL, 495 in U-EXCEED, and 502 in U-ENDURE. A significantly higher percentage of patients who received 45-mg upadacitinib than those who received placebo had clinical remission (in U-EXCEL, 49.5% vs. 29.1%; in U-EXCEED, 38.9% vs. 21.1%) and an endoscopic response (in U-EXCEL, 45.5% vs. 13.1%; in U-EXCEED, 34.6% vs. 3.5%) (P<0.001 for all comparisons). At week 52 in U-ENDURE, a higher percentage of patients had clinical remission with 15-mg upadacitinib (37.3%) or 30-mg upadacitinib (47.6%) than with placebo (15.1%), and a higher percentage had an endoscopic response with 15-mg upadacitinib (27.6%) or 30-mg upadacitinib (40.1%) than with placebo (7.3%) (P<0.001 for all comparisons). Herpes zoster infections occurred more frequently in the 45-mg and 30-mg upadacitinib groups than in the respective placebo groups, and hepatic disorders and neutropenia were more frequent in the 30-mg upadacitinib group than in the other maintenance groups. Gastrointestinal perforations developed in 4 patients who received 45-mg upadacitinib and in 1 patient each who received 30-mg or 15-mg upadacitinib. CONCLUSIONS: Upadacitinib induction and maintenance treatment was superior to placebo in patients with moderate-to-severe Crohn's disease. (Funded by AbbVie; U-EXCEL, U-EXCEED, and U-ENDURE ClinicalTrials.gov numbers, NCT03345849, NCT03345836, and NCT03345823.).

Milk fat globule-epidermal growth factor 8 (MFGE8) prevents intestinal fibrosis.

OBJECTIVE: Intestinal fibrosis is considered an inevitable consequence of chronic IBD, leading to stricture formation and need for surgery. During the process of fibrogenesis, extracellular matrix (ECM) components critically regulate the function of mesenchymal cells. We characterised the composition and function of ECM in fibrostenosing Crohn's disease (CD) and control tissues. DESIGN: Decellularised full-thickness intestinal tissue platforms were tested using three different protocols, and ECM composition in different tissue phenotypes was explored by proteomics and validated by quantitative PCR (qPCR) and immunohistochemistry. Primary human intestinal myofibroblasts (HIMFs) treated with milk fat globule-epidermal growth factor 8 (MFGE8) were evaluated regarding the mechanism of their antifibrotic response, and the action of MFGE8 was tested in two experimental intestinal fibrosis models. RESULTS: We established and validated an optimal decellularisation protocol for intestinal IBD tissues. Matrisome analysis revealed elevated MFGE8 expression in CD strictured (CDs) tissue, which was confirmed at the mRNA and protein levels. Treatment with MFGE8 inhibited ECM production in normal control HIMF but not CDs HIMF. Next-generation sequencing uncovered functionally relevant integrin-mediated signalling pathways, and blockade of integrin αvß5 and focal adhesion kinase rendered HIMF non-responsive to MFGE8. MFGE8 prevented and reversed experimental intestinal fibrosis in vitro and in vivo. CONCLUSION: MFGE8 displays antifibrotic effects, and its administration may represent a future approach for prevention of IBD-induced intestinal strictures.

Comparative analysis of [18F]F-FAPI PET/CT, [18F]F-FDG PET/CT and magnetization transfer MR imaging to detect intestinal fibrosis in Crohn's disease: A prospective animal model and human cohort study.

PURPOSE: Accurately and early detection of intestinal fibrosis in Crohn's disease (CD) is crucial for clinical management yet remains an unmet need. Fibroblast activation protein inhibitor (FAPI) PET/CT has emerged as a promising tool to assess fibrosis. We aimed to investigate the diagnostic capability of [18F]F-FAPI PET/CT in detecting intestinal fibrosis and compared it with[18F]F-FDG PET/CT and magnetization transfer MR imaging (MTI). METHODS: Twenty-two rats underwent TNBS treatment to simulate fibrosis development, followed by three quantitative imaging sessions within one week. Mean and maximum standardized uptake values (SUVmean and SUVmax) were calculated on[18F]F-FAPI and [18F]F-FDG PET/CT, along with normalized magnetization transfer ratio on MTI. Intestinal fibrosis was assessed pathologically, with MTI serving as imaging standard for fibrosis. The diagnostic efficacy of imaging parameters in fibrosis was compared using pathological and imaging standards. Ten patients with 34 bowel strictures were prospectively recruited to validate their diagnostic performance, using the identical imaging protocol. RESULTS: In CD patients, the accuracy of FAPI uptake (both AUCs = 0.87, both P ≤ 0.01) in distinguishing non-to-mild from moderate-to-severe fibrosis was higher than FDG uptake (both AUCs = 0.82, P ≤ 0.01) and comparable to MTI (AUCs = 0.90, P ≤ 0.001). In rats, FAPI uptake responded earlier to fibrosis development than FDG and MTI; consistently, during early phase, FAPI uptake showed a stronger correlation (SUVmean: R = 0.69) with pathological fibrosis than FDG (SUVmean: R = 0.17) and MTI (R = 0.52). CONCLUSION: The diagnostic efficacy of [18F]F-FAPI PET/CT in detecting CD fibrosis is superior to [18F]F-FDG PET/CT and comparable to MTI, exhibiting great potential for early detection of intestinal fibrosis.

The efficacy and safety of fexuprazan in treating erosive esophagitis: a phase III, randomized, double-blind, multicenter study.

BACKGROUND AND AIM: Fexuprazan is a novel potassium-competitive acid blocker (P-CAB). This study aimed to explore the noninferior efficacy and safety of fexuprazan to esomeprazole in treating erosive esophagitis (EE). METHODS: This was a phase III, randomized, double-blind multicenter study. Patients with endoscopically confirmed EE were randomized to receive fexuprazan 40 mg or esomeprazole 40 mg once a daily for 4-8 weeks. The healing rates of EE, symptom response, GERD-health-related quality life (GERD-HRQL), and treatment-emergent adverse events (TEAEs) were compared between fexuprazan group and esomeprazole group. RESULTS: A total of 332 subjects were included in full analysis set (FAS) and 311 in per-protocol set (PPS). The healing rates of fexuprazan and esomeprazole groups at 8 weeks were 88.5% (146/165) and 89.0% (145/163), respectively, in FAS and 97.3% (145/149) and 97.9% (143/146), respectively, in PPS. Noninferiority of fexuprazan compared with esomeprazole according to EE healing rates at 8 weeks was demonstrated in both FAS and PPS analysis. No significant difference was found between groups in EE healing rates at 4 weeks, symptom responses, and changes of GERD-HRQL. The incidence of drug-related AEs was 19.4% (32/165) in fexuprazan arm and 19.6% (32/163) in esomeprazole arm. CONCLUSION: This study demonstrated noninferior efficacy of fexuprazan to esomeprazole in treating EE. The incidence of TEAEs was similar between fexuprazan and esomeprazole. Trial registration number NCT05813561.

Pharmacokinetics, Safety, and Tolerability of Tenapanor in Healthy Chinese and Caucasian Volunteers: A Randomized, Open-Label, Single-Center, Placebo-Controlled Phase 1 Study.

Background: Tenapanor is a locally acting selective sodium-hydrogen exchanger 3 inhibitor with the potential to treat sodium/phosphorus and fluid overload in various cardiac-renal diseases, which has been approved for constipation-predominant irritable bowel syndrome in the US. The pharmacokinetics (PK) of tenapanor and its metabolite tenapanor-M1 (AZ13792925), as well as the safety and tolerability of tenapanor, were investigated in healthy Chinese and Caucasian subjects. Methods: This randomized, open-label, single-center, placebo-controlled phase 1 study (https://www.chinadrugtrials.org.cn; CTR20201783) enrolled Chinese and Caucasian healthy volunteers into 4 parallel cohorts (3 cohorts for Chinese subjects, 1 cohort for Caucasian subjects). In each cohort, 15 subjects were expected to be included and received oral tenapanor (10 or 30 mg as single dose, or 50 mg as a single dose followed by a twice-daily repeated dose from Day 5 to 11, with a single dose in the morning on Day 11) or placebo in a 4 : 1 ratio. Results: 59 healthy volunteers received tenapanor 10 mg (n = 12 Chinese), 30 mg (n = 12 Chinese), or 50 mg (n = 12 (Chinese), n = 11 (Caucasian)) or placebo (n = 12, 3 per cohort). After single and twice-daily repeated doses, tenapanor plasma concentrations were all below the limit of quantitation; tenapanor-M1 appeared slowly in plasma. In single-ascending dose evaluation (10 to 50 mg) of Chinese subjects, the mean Cmax, AUC0-t, and AUC0-∞ of tenapanor-M1 increased with increasing dose level, and AUC0-t increased approximately dose proportionally. The Cmax accumulation ratio was 1.55 to 6.92 after 50 mg repeated dose in Chinese and Caucasian subjects. Exposure to tenapanor-M1 was generally similar between the Chinese and Caucasian subjects. Tenapanor was generally well-tolerated and the safety profile was similar between the Chinese and Caucasian participants receiving tenapanor 50 mg, as measured by vital signs, physical and laboratory examination, 12-lead ECG, and adverse events. No serious adverse event or adverse event leading to withdrawal occurred. Conclusion: Tenapanor was well-tolerated, with similar PK and safety profiles between Chinese and Caucasian subjects. This trial is registered with CTR20201783.

International clinical practice guideline on the use of traditional Chinese medicine for ulcerative colitis by Board of Specialty Committee of Digestive System Disease of World Federation of Chinese Medicine Societies (2023).

Ulcerative colitis (UC), a chronic and nonspecific inflammatory disease of the intestine, has become a prevalent global health concern. This guideline aims to equip clinicians and caregivers with effective strategies for the treatment and management of adult UC patients using traditional Chinese medicine (TCM). The guideline systematically evaluated contemporary evidence through the Grading of Recommendations Assessment, Development, and Evaluation framework. Additionally, it incorporated insights from ancient Chinese medical sources, employing the evidence grading method found in traditional TCM literature. The development process involved collaboration with multidisciplinary experts and included input from patients with UC. The guideline, based on a comprehensive review of available evidence, present 40 recommendations. They offer a condensed overview of TCM's role in understanding the pathogenesis, diagnosis, and treatment of UC, along with an assessment of the efficacy of various TCM-based treatments. TCM exhibits promising outcomes in the treatment of UC. However, to establish its efficacy conclusively, further high-quality clinical studies on TCM for UC are essential.

Special issue "The advance of solid tumor research in China": Prediction of Sunitinib efficacy using computed tomography in patients with pancreatic neuroendocrine tumors.

Clinically effective methods to predict the efficacy of sunitinib, for patients with metastatic or locally advanced pancreatic neuroendocrine tumors (panNET) are scarce, making precision treatment difficult. This study aimed to develop and validate a computed tomography (CT)-based method to predict the efficacy of sunitinib in patients with panNET. Pretreatment CT images of 171 lesions from 38 patients with panNET were included. CT value ratio (CT value of tumor/CT value of abdominal aorta from the same patient) and radiomics features were extracted for model development. Receiver operating curve (ROC) with area under the curve (AUC) and decision curve analysis (DCA) were used to evaluate the proposed model. Tumor shrinkage of >10% at first follow-up after sunitinib treatment was significantly associated with longer progression-free survival (PFS; P < .001) and was used as the major treatment outcome. The CT value ratio could predict tumor shrinkage with AUC of 0.759 (95% confidence interval [CI], 0.685-0.833). We then developed a radiomics signature, which showed significantly higher AUC in training (0.915; 95% CI, 0.866-0.964) and validation (0.770; 95% CI, 0.584-0.956) sets than CT value ratio. DCA also confirmed the clinical utility of the model. Subgroup analysis showed that this radiomics signature had a high accuracy in predicting tumor shrinkage both for primary and metastatic tumors, and for treatment-naive and pretreated tumors. Survival analysis showed that radiomics signature correlated with PFS (P = .020). The proposed radiomics-based model accurately predicted tumor shrinkage and PFS in patients with panNET receiving sunitinib and may help select patients suitable for sunitinib treatment.

Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials.

BACKGROUND: There is a great unmet need for advanced therapies that provide rapid, robust, and sustained disease control for patients with ulcerative colitis. We assessed the efficacy and safety of upadacitinib, an oral selective Janus kinase 1 inhibitor, as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. METHODS: This phase 3, multicentre, randomised, double-blind, placebo-controlled clinical programme consisted of two replicate induction studies (U-ACHIEVE induction [UC1] and U-ACCOMPLISH [UC2]) and a single maintenance study (U-ACHIEVE maintenance [UC3]). The studies were conducted across Europe, North and South America, Australasia, Africa, and the Asia-Pacific region at 199 clinical centres in 39 countries (UC1), 204 clinical centres in 40 countries (UC2), and 195 clinical centres in 35 countries (UC3). Patients aged 16-75 years with moderately to severely active ulcerative colitis (Adapted Mayo score 5-9; endoscopic subscore 2 or 3) for at least 90 days were randomly assigned (2:1) to oral upadacitinib 45 mg once daily or placebo for 8 weeks (induction studies). Patients who achieved clinical response following 8-week upadacitinib induction were re-randomly assigned (1:1:1) to upadacitinib 15 mg, upadacitinib 30 mg, or placebo for 52 weeks (maintenance study). All patients were randomly assigned using web-based interactive response technology. The primary endpoints were clinical remission per Adapted Mayo score at week 8 (induction) and week 52 (maintenance). The efficacy analyses in the two induction studies were based on the intent-to-treat population, which included all randomised patients who received at least one dose of treatment. In the maintenance study, the primary efficacy analyses reported in this manuscript were based on the first 450 (planned) clinical responders to 8-week induction therapy with upadacitinib 45 mg once daily. The safety analysis population in the induction studies consisted of all randomised patients who received at least one dose of treatment; in the maintenance study, this population included all patients who received at least one dose of treatment as part of the primary analysis population. These studies are registered at ClinicalTrials.gov, NCT02819635 (U-ACHIEVE) and NCT03653026 (U-ACCOMPLISH). FINDINGS: Between Oct 23, 2018, and Sept 7, 2020, 474 patients were randomly assigned to upadacitinib 45 mg once daily (n=319) or placebo (n=155) in UC1. Between Dec 6, 2018, and Jan 14, 2021, 522 patients were randomly assigned to upadacitinib 45 mg once daily (n=345) or placebo (n=177) in UC2. In UC3, a total of 451 patients (21 from the phase 2b study, 278 from UC1, and 152 from UC2) who achieved a clinical response after 8 weeks of upadacitinib induction treatment were randomly assigned again to upadacitinib 15 mg (n=148), upadacitinib 30 mg (n=154), and placebo (n=149) in the primary analysis population. Statistically significantly more patients achieved clinical remission with upadacitinib 45 mg (83 [26%] of 319 patients in UC1 and 114 [34%] of 341 patients in UC2) than in the placebo group (seven [5%] of 154 patients in UC1 and seven [4%] of 174 patients; p<0·0001; adjusted treatment difference 21·6% [95% CI 15·8-27·4] for UC1 and 29·0% [23·2-34·7] for UC2). In the maintenance study, clinical remission was achieved by statistically significantly more patients receiving upadacitinib (15 mg 63 [42%] of 148; 30 mg 80 [52%] of 154) than those receiving placebo (18 [12%] of 149; p<0·0001; adjusted treatment difference 30·7% [21·7-39·8] for upadacitinib 15 mg vs placebo and 39·0% [29·7-48·2] for upadacitinib 30 mg vs placebo). The most commonly reported adverse events in UC1 were nasopharyngitis (15 [5%] of 319 in the upadacitinib 45 mg group vs six [4%] of 155 in the placebo group), creatine phosphokinase elevation (15 [4%] vs three [2%]), and acne (15 [5%] vs one [1%]). In UC2, the most frequently reported adverse event was acne (24 [7%] of 344 in the upadacitinib 45 mg group vs three [2%] of 177 in the placebo group). In both induction studies, serious adverse events and adverse events leading to discontinuation of treatment were less frequent in the upadacitinib 45 mg group than in the placebo group (serious adverse events eight [3%] vs nine (6%) in UC1 and 11 [3%] vs eight [5%] in UC2; adverse events leading to discontinuation six [2%] vs 14 [9%] in UC1 and six [2%] vs nine [5%] in UC2). In UC3, the most frequently reported adverse events (≥5%) were worsening of ulcerative colitis (19 [13%] of 148 in the upadacitinib 15 mg group vs 11 [7%] of 154 in the upadacitinib 30 mg group vs 45 [30%] of 149 in the placebo group), nasopharyngitis (18 [12%] vs 22 [14%] vs 15 [10%]), creatine phosphokinase elevation (nine [6%] vs 13 [8%] vs three [2%]), arthralgia (nine [6%] vs five [3%] vs 15 [10%]), and upper respiratory tract infection (seven [5%] vs nine [6%] vs six [4%]). The proportion of serious adverse events (ten [7%] vs nine [6%] vs 19 [13%]) and adverse events leading to discontinuation (six [4%] vs ten [6%] vs 17 [11%]) was lower in both upadacitinib groups than in the placebo group. Events of cancer, adjudicated major adverse cardiac events, or venous thromboembolism were reported infrequently. There were no treatment-related deaths. INTERPRETATION: Upadacitinib demonstrated a positive efficacy and safety profile and could be an effective treatment option for patients with moderately to severely active ulcerative colitis. FUNDING: AbbVie.

The Mutational, Prognostic, and Therapeutic Landscape of Neuroendocrine Neoplasms.

BACKGROUND: Neuroendocrine neoplasms (NENs) represent clinically and genetically heterogeneous malignancies, thus a comprehensive understanding of underlying molecular characteristics, prognostic signatures, and potential therapeutic targets is urgently needed. METHODS: Next-generation sequencing (NGS) and immunohistochemistry were applied to acquire genomic and immune profiles of NENs from 47 patients. RESULTS: Difference was distinguished based on differentiation grade and primary localization. Poorly differentiated neuroendocrine carcinomas (NECs) and well-differentiated neuroendocrine tumors (NETs) harbored distinct molecular features; we observed that tumor mutational burden (TMB) and tumor neoantigen burden (TNB) were significantly higher in NECs versus NETs. Notably, we identified a 7-gene panel (MLH3, NACA, NOTCH1, NPAP1, RANBP17, TSC2, and ZFHX4) as a novel prognostic signature in NENs; patients who carried mutations in any of the 7 genes exhibited significantly poorer survival. Furthermore, loss of heterozygosity (LOH) and germline homogeneity in human leukocyte antigen (HLA) are common in NENs, accounting for 39% and 36%, respectively. Notably, HLA LOH was an important prognostic biomarker for a subgroup of NEN patients. Finally, we analyzed clinically actionable targets in NENs, revealing that TMB high (TMB-H) or gene mutations in TP53, KRAS, and HRAS were the most frequently observed therapeutic indicators, which granted eligibility to immune checkpoint blockade (ICB) and targeted therapy. CONCLUSION: Our study revealed heterogeneity of NENs, and identified novel prognostic signatures and potential therapeutic targets, which directing improvements of clinical management for NEN patients in the foreseeable future.

Efficacy of Biologic Drugs in Short-Duration Versus Long-Duration Inflammatory Bowel Disease: A Systematic Review and an Individual-Patient Data Meta-Analysis of Randomized Controlled Trials.

BACKGROUND AND AIMS: Starting biologic treatment early in the course of inflammatory bowel disease (IBD) may be associated with higher efficacy, especially in Crohn's disease (CD). METHODS: This was a systematic review and individual-patient data meta-analysis of all placebo-controlled trials of biologics approved for IBD at study inception (October 2015), using Vivli data-sharing platform. The primary outcome was the proportional biologic/placebo treatment effect on induction of remission in patients with short-duration (≤18 months) vs long-duration disease (>18 months) analyzed separately for CD and ulcerative colitis (UC). We used meta-regression to examine the impact of patients' characteristics on the primary outcome. RESULTS: We included 25 trials, testing infliximab, adalimumab, certolizumab, golimumab, natalizumab, or vedolizumab (6168 patients with CD and 3227 patients with UC). In CD, remission induction rates were higher in pooled placebo and patients in active arms with short-duration disease of ≤18 months (41.4% [244 of 589]) compared with disease duration of >18 months (29.8% [852 of 2857], meta-analytically estimated odds ratio, 1.33; 95% confidence interval, 1.09-1.64). The primary outcome, proportional biologic/placebo treatment effect on induction of remission, was not different in short-duration disease of ≤18 months (n = 589, odds ratio, 1.47; 95% confidence interval, 1.01-2.15) compared with longer disease duration (n = 2857, odds ratio, 1.43; 95% confidence interval, 1.19-1.72). In UC trials, both the proportional biologic/placebo remission-induction effect and the pooled biologic-placebo effect were stable, regardless of disease duration. Primary outcome results remained unchanged when tested using alternative temporal cutoffs and when modeled for individual patient's covariates, including prior anti-tumor necrosis factor exposure. CONCLUSIONS: There are higher rates of induction of remission with biologics and with placebo in early CD, resulting in a treatment to placebo effect ratio that is similar across disease durations. No such relationships between disease duration and outcomes was found in UC. PROSPERO registration: CRD42018041961.

Efficacy and Safety of Ivarmacitinib in Patients With Moderate-to-Severe, Active, Ulcerative Colitis: A Phase II Study.

BACKGROUND & AIMS: Current therapies for ulcerative colitis (UC) fail to achieve satisfactory disease control. Selective inhibition of Janus kinase (JAK) type 1 may improve clinical outcomes in patients with UC while avoiding the side effects associated with pan-JAK inhibition. The safety and efficacy of the selective JAK1 inhibitor ivarmacitinib (formerly SHR0302) were evaluated in patients with moderate-to-severe, active UC. METHODS: AMBER2 was a double-blind, placebo-controlled, phase II trial conducted at 63 clinical centers in China, the United States, and Europe. Patients (N = 164) were randomized 1:1:1:1 to receive oral ivarmacitinib 8 mg once daily (QD), 4 mg twice daily (BID), or 4 mg QD, or placebo for 8 weeks, followed by an 8-week extension period. The primary endpoint was clinical response rate at week 8. Hochberg's procedure was used to control the study-wise type 1 error at alpha=0.1. RESULTS: A total of 146 (89.0%) patients completed 8 weeks of treatment. Week 8 clinical response rates were significantly higher in the 8 mg QD (46.3%; P = .066), 4 mg BID (46.3%; P = .059), and 4 mg QD (43.9%; P = .095) groups vs placebo (26.8%). Week 8 rates of clinical remission were 22.0% (P = .020), 24.4% (P = .013), and 24.4% (P = .011) in the 3 ivarmacitinib treatment groups, respectively, vs 4.9% for placebo. During the initial 8-week period, treatment-emergent adverse events occurred in 43.9% to 48.8% of ivarmacitinib-treated patients and in 39.0% of the placebo group, and were predominantly mild. There were no deaths, or major adverse cardiovascular or thromboembolic events. CONCLUSION: Ivarmacitinib demonstrated clinical efficacy and was well tolerated in patients with moderate-to-severe, active, UC. Ivarmacitinib represents a promising new treatment for moderate-to-severe UC. CLINICALTRIALS: gov number, NCT03675477.

Decreased TMIGD1 aggravates colitis and intestinal barrier dysfunction via the BANF1-NF-κB pathway in Crohn's disease.

BACKGROUND: Disrupted intestinal epithelial barrier is one of the major causes of Crohn's disease (CD). Novel molecular targets for intestinal epithelial barrier are essential to treatment of CD. Transmembrane and immunoglobulin domain-containing protein 1 (TMIGD1) is an adhesion molecule that regulates cell adhesion, migration, and enterocyte differentiation. However, the function and mechanism of TMIGD1 in CD and intestinal epithelial barrier has rarely been studied. Furthermore, the association between TMIGD1 and the clinical features of CD remains unclear. METHODS: Transcriptome analysis on colonic mucosa from CD patients and healthy individuals were performed to identify dysregulated genes. Multi-omics integration of the 1000IBD cohort including genomics, transcriptomics of intestinal biopsies, and serum proteomics identified the association between genes and characteristics of CD. Inflammation was assessed by cytokine production in cell lines, organoids and intestinal-specific Tmigd1 knockout (Tmigd1INT-KO) mice. Epithelial barrier integrity was evaluated by trans-epithelium electrical resistance (TEER), paracellular permeability, and apical junction complex (AJC) expression. Co-immunoprecipitation, GST pull-down assays, mass spectrometry, proteomics, and transcriptome analysis were used to explore downstream mechanisms. RESULTS: Multi-omics integration suggested that TMIGD1 was negatively associated with inflammatory characteristics of CD. TMIGD1 was downregulated in inflamed intestinal mucosa of patients with CD and mice colitis models. Tmigd1INT-KO mice were more susceptible to chemically induced colitis. In epithelial cell lines and colonic organoids, TMIGD1 knockdown caused impaired intestinal barrier integrity evidenced by increased paracellular permeability and reduced TEER and AJC expression. TMIGD1 knockdown in intestinal epithelial cells also induced pro-inflammatory cytokine production. Mechanistically, TMIGD1 directly interacted with cytoplasmic BAF nuclear assembly factor 1 (BANF1) to inhibit NF-κB activation. Exogenous expression of TMIGD1 and BANF1 restored intestinal barrier function and inhibited inflammation in vitro and in vivo. TMIGD1 expression predicted response to anti-TNF treatment in patients with CD. CONCLUSIONS: Our study demonstrated that TMIGD1 maintained intestinal barrier integrity and inactivated inflammation, and was therefore a potential therapeutic target for CD.

Oxidative stress gene expression, DNA methylation, and gut microbiota interaction trigger Crohn's disease: a multi-omics Mendelian randomization study.

BACKGROUND: Oxidative stress (OS) is a key pathophysiological mechanism in Crohn's disease (CD). OS-related genes can be affected by environmental factors, intestinal inflammation, gut microbiota, and epigenetic changes. However, the role of OS as a potential CD etiological factor or triggering factor is unknown, as differentially expressed OS genes in CD can be either a cause or a subsequent change of intestinal inflammation. Herein, we used a multi-omics summary data-based Mendelian randomization (SMR) approach to identify putative causal effects and underlying mechanisms of OS genes in CD. METHODS: OS-related genes were extracted from the GeneCards database. Intestinal transcriptome datasets were collected from the Gene Expression Omnibus (GEO) database and meta-analyzed to identify differentially expressed genes (DEGs) related to OS in CD. Integration analyses of the largest CD genome-wide association study (GWAS) summaries with expression quantitative trait loci (eQTLs) and DNA methylation QTLs (mQTLs) from the blood were performed using SMR methods to prioritize putative blood OS genes and their regulatory elements associated with CD risk. Up-to-date intestinal eQTLs and fecal microbial QTLs (mbQTLs) were integrated to uncover potential interactions between host OS gene expression and gut microbiota through SMR and colocalization analysis. Two additional Mendelian randomization (MR) methods were used as sensitivity analyses. Putative results were validated in an independent multi-omics cohort from the First Affiliated Hospital of Sun Yat-sen University (FAH-SYS). RESULTS: A meta-analysis from six datasets identified 438 OS-related DEGs enriched in intestinal enterocytes in CD from 817 OS-related genes. Five genes from blood tissue were prioritized as candidate CD-causal genes using three-step SMR methods: BAD, SHC1, STAT3, MUC1, and GPX3. Furthermore, SMR analysis also identified five putative intestinal genes, three of which were involved in gene-microbiota interactions through colocalization analysis: MUC1, CD40, and PRKAB1. Validation results showed that 88.79% of DEGs were replicated in the FAH-SYS cohort. Associations between pairs of MUC1-Bacillus aciditolerans and PRKAB1-Escherichia coli in the FAH-SYS cohort were consistent with eQTL-mbQTL colocalization. CONCLUSIONS: This multi-omics integration study highlighted that OS genes causal to CD are regulated by DNA methylation and host-microbiota interactions. This provides evidence for future targeted functional research aimed at developing suitable therapeutic interventions and disease prevention.

The role of quantitative tumor burden based on [68 Ga]Ga-DOTA-NOC PET/CT in well-differentiated neuroendocrine tumors: beyond prognosis.

PURPOSE: We aimed to elucidate the role of quantitative tumor burden based on PET/CT of somatostatin receptors in well-differentiated neuroendocrine tumors (NETs). METHODS: This study enrolled patients with [68 Ga]Ga-DOTA-NOC PET/CT-positive advanced NETs who did not receive medical treatment prior to PET/CT. Tumor burden was calculated using methods based on the background threshold and relative fixed threshold values (30%, 40%, and 50%). The prognostic value of the measured tumor burden in reference to overall survival (OS) and progression-free survival (PFS) on treatment with octreotide long-acting repeatable (LAR) was assessed using Cox regression analysis, Harrell's C-index, and survival analysis. A classification and regression tree (CART) was used to determine the optimal threshold for tumor burden. RESULTS: A total of 204 patients were included. Somatostatin receptor-expressing tumor volume (SRETV) and liver SRETV derived from a relative fixed threshold of 30% (SRETV30 and liver SRETV30) were statistically significantly associated with OS (C-index: 0.802 [95% confidence interval (CI), 0.658-0.946] and 0.806 [95% CI, 0.664-0.948], respectively). Extrahepatic tumor burden was not correlated with OS (hazard ratio: 0.617, 95% CI: 0.241-1.574, P = 0.312). Among 155 patients with non-functional NETs with a ki-67 index of ≤ 10%, those with a high SRETV30 (P = 0.016) or high liver SRETV30 (P = 0.014) showed statistically significantly worse PFS on treatment with octreotide LAR. Patients receiving a higher dose of octreotide LAR normalized by SRETV30 or liver SRETV30 (a normalized dose or a liver normalized dose) showed prolonged PFS on treatment with octreotide LAR and a prolonged OS. CONCLUSION: Quantitative tumor burden based on [68 Ga]Ga-DOTA-NOC PET/CT was correlated with OS and PFS in patients with non-functional NETs with a ki-67 index of ≤ 10% who received octreotide LAR. Calculating normalized and liver normalized doses may help in selecting the starting dose of octreotide LAR.

Circulating Regulatory T Cells: A Novel Marker Associated with Liver Metastasis and the Treatment Response of Transarterial Embolization in Gastroenteropancreatic Neuroendocrine Tumors.

INTRODUCTION: To investigate the role of circulating regulatory T cells (Tregs) as a novel marker associated with liver metastases and treatment response to transarterial embolization (TAE) in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). METHODS: Circulating Tregs, defined as the CD4+CD25+CD127low/- population, were examined by flow cytometry in peripheral blood mononuclear cells (PBMCs) from patients with GEP-NETs. Clinicopathological parameters, radiologic response, and hepatic progression-free survival (hPFS) data were collected. RESULTS: The association between circulating Tregs and clinicopathological parameters was analyzed in 139 GEP-NET patients. Higher Treg levels were significantly associated with more progressive clinical features, including a higher WHO grade, more advanced TNM stage, and the presence of liver metastases. A Treg level ≥ 8.015% distinguished between patients with and without liver metastases. Among a cohort of 51 GEP-NET patients who were subjected to TAE for reducing liver metastasis burden, patients with higher Treg levels depicted unfavorable responses and significantly reduced hPFS after TAE treatment. We also revealed that patients with Treghigh (≥8.975%) displayed significantly shorter median hPFS than patients with Treglow (< 8.975%). Additionally, after adjusting for other confounding clinical parameters, the association between Tregs and treatment response as well as hPFS remained significant, suggesting that Tregs may have a strong and independent prognostic impact in GEP-NETs. CONCLUSIONS: Our data suggest that circulating Tregs are a novel immunological marker associated with liver metastases and treatment response to TAE in patients with GEP-NETs.

Bile acid alterations associated with indolent course of inflammatory bowel disease.

BACKGROUND: The indolent course of treatment-naive patients with inflammatory bowel disease (IBD) is confirmed predictable based on clinical characteristics. Current evidences supported that bile acids (BAs) alteration might be promising biomarkers in the field of IBD. We aimed to analyze the alterations of BAs as the disease progresses and explore their predictive value for indolent course of IBD. METHODS: The indolent course of IBD was defined as a disease course without need for strict interventions throughout the entire follow-up. A targeted metabolomics method was used to detect the concentration of 27 BAs from serum sample in treatment-naive patients with IBD (Crohn's disease [CD], n = 27; ulcerative colitis [UC], n = 50). Patients with CD and UC were individually divided into two groups for further study according to the median time of indolent course. The overall BAs profile and the clinical value of BAs in predicting indolent course of IBD were identified between different groups. RESULTS: For CD, the levels of deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, glycolithocholic acid-3-sulfate disodium salt and iso-lithocholic acid were significantly increased in patients with indolent course > 18 M (p < 0.05). These five BAs owned 83.5% accuracy for predicting indolent course over 18 months in CD. For UC, the concentration of deoxycholic acid and glycodeoxycholic acid were significantly higher, while dehydrocholic acid were lower in patients with indolent course > 48 M (p < 0.05). These three BAs predicted indolent course over 48 months of 69.8% accuracy in UC. CONCLUSION: The specific BAs alterations might be potential biomarkers in predicting disease course of IBD patients.

Asia-Pacific guidelines for managing functional dyspepsia overlapping with other gastrointestinal symptoms.

Contemporary systems for the diagnosis and management gastrointestinal symptoms not attributable to organic diseases (Functional GI Disorders, FGID, now renamed Disorders of Gut-Brain Interaction, DGBI) seek to categorize patients into narrowly defined symptom-based sub-classes to enable targeted treatment of patient cohorts with similar underlying putative pathophysiology. However, an overlap of symptom categories frequently occurs and has a negative impact on treatment outcomes. There is a lack of guidance on their management. An Asian Pacific Association of Gastroenterology (APAGE) working group was set up to develop clinical practice guidelines for management of patients with functional dyspepsia (FD) who have an overlap with another functional gastrointestinal disorder: FD with gastroesophageal reflux (FD-GERD), epigastric pain syndrome with irritable bowel syndrome (EPS-IBS), postprandial distress syndrome with IBS (PDS-IBS), and FD-Constipation. We identified putative pathophysiology to provide a basis for treatment recommendations. A management algorithm is presented to guide primary and secondary care clinicians.

Effect of Induction Therapy With Olamkicept vs Placebo on Clinical Response in Patients With Active Ulcerative Colitis: A Randomized Clinical Trial.

Importance: Olamkicept, a soluble gp130-Fc-fusion-protein, selectively inhibits interleukin 6 (IL-6) trans-signaling by binding the soluble IL-6 receptor/IL-6 complex. It has anti-inflammatory activities in inflammatory murine models without immune suppression. Objective: To assess the effect of olamkicept as induction therapy in patients with active ulcerative colitis. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled phase 2 trial of olamkicept in 91 adults with active ulcerative colitis (full Mayo score ≥5, rectal bleeding score ≥1, endoscopy score ≥2) and an inadequate response to conventional therapy. The study was conducted at 22 clinical study sites in East Asia. Patients were recruited beginning in February 2018. Final follow-up occurred in December 2020. Interventions: Eligible patients were randomized 1:1:1 to receive a biweekly intravenous infusion of olamkicept 600 mg (n = 30) or 300 mg (n = 31) or placebo (n = 30) for 12 weeks. Main Outcomes and Measures: The primary end point was clinical response at week 12 (defined as ≥3 and ≥30% decrease from baseline total Mayo score; range, 0-12 [worst] with ≥1 decrease and ≤1 in rectal bleeding [range, 0-3 {worst}]). There were 25 secondary efficacy outcomes, including clinical remission and mucosal healing at week 12. Results: Ninety-one patients (mean age, 41 years; 25 women [27.5%]) were randomized; 79 (86.8%) completed the trial. At week 12, more patients receiving olamkicept 600 mg (17/29 [58.6%]) or 300 mg (13/30 [43.3%]) achieved clinical response than placebo (10/29 [34.5%]), with adjusted difference vs placebo of 26.6% (90% CI, 6.2% to 47.1%; P = .03) for 600 mg and 8.3% (90% CI, -12.6% to 29.1%; P = .52) for 300 mg. Among patients randomized to receive 600 mg olamkicept, 16 of 25 secondary outcomes were statistically significant compared with placebo. Among patients randomized to receive 300 mg, 6 of 25 secondary outcomes were statistically significant compared with placebo. Treatment-related adverse events occurred in 53.3% (16/30) of patients receiving 600 mg olamkicept, 58.1% (18/31) receiving 300 mg olamkicept, and 50% (15/30) receiving placebo. The most common drug-related adverse events were bilirubin presence in the urine, hyperuricemia, and increased aspartate aminotransferase levels, and all were more common in the olamkicept groups compared with placebo. Conclusions and Relevance: Among patients with active ulcerative colitis, biweekly infusion of olamkicept 600 mg, but not 300 mg, resulted in a greater likelihood of clinical response at 12 weeks compared with placebo. Further research is needed for replication and to assess longer-term efficacy and safety. Trial Registration: ClinicalTrials.gov Identifier: NCT03235752.