Background: Hereditary angioedema (HAE) is a rare, severe, disabling, and life-threatening disorder characterized by recurrent and unpredictable edema of skin and mucous membranes. Gastrointestinal edema, often presenting as abdominal pain, is common but frequently misdiagnosed, leading to unnecessary surgeries. This study aims to characterize gastrointestinal edema in HAE patients to improve early diagnosis and guide treatment. Method: We analyzed 61 patients with HAE who were admitted in our hospital between April 1, 2023 and August 31, 2025. Data on demographic characteristics, clinical manifestations, laboratory findings, imaging results, and treatment outcomes were collected through questionnaires and hospital electronic records. Result: Among the patients, 86.9% experienced gastrointestinal edema, mostly characterized by abdominal pain (94.3%), nausea (79.2%), and diarrhea (71.7%). Misdiagnosis occurred in 73.6% of cases, and 22.6% underwent unnecessary surgeries. The median age of gastrointestinal edema onset was 16.0 years, with the most severe episodes occurring at a median age of 25.0 years. The median annual frequency of attacks was 4.0/year, with a median severity score of 7.0. Acute attacks showed elevated D-dimer, white blood cells, neutrophils, and hemoglobin. CT imaging frequently revealed intestinal wall thickening and abdominal-pelvic effusion. Lanadelumab demonstrated superior efficacy over danazol in reducing both the frequency and severity of edema attacks, while icatibant significantly shortened the duration of edema episodes. Conclusion: This study updates the clinical and imaging features of gastrointestinal edema in Chinese patients with HAE, identifies biomarkers of gastrointestinal edema attacks, and highlights the efficacy of lanadelumab and icatibant, aiding timely diagnosis and treatment.

BackgroundCytotoxic T-Lymphocyte-Associated Protein 4 (CTLA4) haploinsufficiency is a rare monogenic immunodysregulatory disorder that can affect multiple organ systems, leading to a combination of autoimmunity, immunodeficiency, and lymphoproliferation. It is caused by heterozygous germline mutations of CTLA4, yet the structure-function relationships underlying individual pathogenic variants remain incompletely understood.MethodsWe performed whole-exome sequencing on a patient with adolescent-onset autoimmune enteropathy, early-onset gastric malignancy and multisystem comorbidities, who was initially misdiagnosed with Crohn’s disease and refractory to multiple biologics. Functional assays assessed CTLA4 dimerization and CD80/CD86 binding capacity. Peripheral blood immunophenotyping was conducted using CyTOF and flow cytometry. Intestinal histopathology was evaluated by immunohistochemistry. The patient subsequently received targeted therapy with abatacept.ResultsA novel heterozygous missense variant in CTLA4 (c.167T>G, p.Phe56Cys) was identified. Functional assays demonstrated that this variant impairs CTLA4 protein dimerization and its binding capacity to CD80/CD86, establishing loss-of-function as the molecular basis of pathogenicity. Comprehensive peripheral blood immunophenotyping by CyTOF revealed a broad adaptive immune dysregulation landscape, characterized by depletion of regulatory T cells (Tregs), γδ T cells, and CD161+ cytotoxic-like CD8+ T cells. Flow cytometry confirmed reduction in CD4+CD25+Foxp3+ Treg cells along with decreased CTLA4 expression. Intestinal histopathology showed crypt apoptosis with T cell-predominant infiltration, distinct from classic inflammatory bowel disease. Notably, targeted therapy with abatacept partially restored Treg frequency and alleviated clinical symptoms.ConclusionThese findings identify p.Phe56Cys as a novel loss-of-function CTLA4 variant that disrupts protein dimerization and ligand binding, expanding the mechanistic understanding of CTLA4 haploinsufficiency and supporting genetic screening in patients with refractory autoimmune enteropathy and early-onset gastric malignancy.

BACKGROUND:Crohn disease (CD) is a chronic, recurrent inflammatory bowel disease. Mesenchymal stem cell-derived exosomes (MSC-Exos) have emerged as promising cell-free treatments for CD. OBJECTIVE:In this study we aimed to investigate the therapeutic effect and potential mechanisms of MSC-Exos derived from induced pluripotent stem cells (iPSCs) (iPSC-MSC-Exos) in patients with colitis. METHODS:iPSC-MSC-Exos were administered intraperitoneally to mice with trinitrobenzene sulfonic acid (TNBS)-induced colitis. The colonic stem cell markers Lgr5 and Bmi1, and the proliferation marker Ki-67 were assessed by immunofluorescence. Lamina propria mononuclear cells (LPMCs) were isolated from the mouse colons and analyzed by flow cytometry. Furthermore, microarray analysis was performed to identify the differential expression of micro RNAs (miRNAs) in the iPSC-MSC-Exos. iPSC-MSC-Exos with micro RNA (miR)-34a-5p overexpression (Exo-OE) or knockdown (Exo-KD) were used to treat colitis in the mice. The candidate targets of miR-34a-5p and its downstream signaling pathways were confirmed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blotting. RESULTS:The iPSC-MSC-Exos migrated to the inflamed colon and protected the colon stem cells against inflammatory damage, promoted epithelial cell proliferation, and decreased the infiltration of proinflammatory Th1/9/17, CD4 +  tumor necrosis factor alpha (TNF-α)+, and macrophage cells while increasing anti-inflammatory T-regulatory (Treg) and B-regulatory (Breg) cells to alleviate TNBS-induced colitis in the mice. The therapeutic effect was sustained for 7 days after a single injection. MiR-34a-5p Exo-OE magnified this effect, whereas Exo-KD abolished it. The iPSC-MSC-Exos also inhibited the proliferation and migration of CD4 + LPMCs isolated from patients with CD. The miR-34a-5p expression was significantly elevated in the iPSC-MSC-Exos, which inhibited PPP2R3A expression by directly targeting its 3' untranslated region (3'-UTR). MiR-34a-5p Exo-OE significantly decreased the expression of PPP2R3A while increasing the expression of the Wingless-related integration site (Wnt) signaling ligands of β-catenin (Wnt/β-catenin signaling) and CD44. CONCLUSIONS:iPSC-MSC-Exos ameliorated colitis and promoted mucosal healing in a TNBS-induced CD-like model by activating Wnt/β-catenin signaling via miR-34a-5p, which targets PPP2R3A.

BACKGROUND:Crohn disease (CD) is frequently complicated by intestinal strictures, which require early recognition and management. This study aimed to identify biomarkers associated with CD-related strictures by use of serum and intestinal proteomics and to develop diagnostic and predictive models for potential clinical application. METHODS:Serum samples from treatment-naive CD patients and paired intestinal samples from stricturing intestine were subjected to proteomic analysis. Machine learning approaches were employed to select stricture-related biomarkers and develop models. The candidate protein was validated using external cohorts and molecular experiments. RESULTS:The discovery cohort included 62 patients. A diagnostic model for intestinal stricture was developed using serum levels of 5 proteins from 30 nonstricturing, nonpenetrating (B1) phenotype and 20 stricturing (B2) phenotype patients, achieving an area under the curve of 0.754. A predictive model for stricture progression, based on another set of 5 proteins in 10 B1 progressors, achieved an AUC of 0.947 internally. Serum enzyme-linked immunoassay (ELISA) validation in the First Affiliated Hospital of Sun Yat-sen University (FAH-SYSU) and Sir Run Run Shaw Hospital (SRRSH) cohorts (n = 62) confirmed elevated glypican-6 (GPC6) levels in the stricturing (B2) group, with a similar trend observed in intestinal tissue in the progression group of the RISK cohort (n = 237). Single-cell transcriptomic analysis and immunofluorescence staining further confirmed higher GPC6 expression and protein levels in the fibrostenotic mucosa and submucosa, particularly in fibroblasts. CONCLUSIONS:We developed serum-based diagnostic and predictive models for intestinal strictures in CD, which may be suitable for clinical use once externally adequately validated. GPC6 emerged as a candidate biomarker closely associated with intestinal fibrosis, offering promising implications for its diagnosis and prognosis.

Monogenic errors of immunity can present with inflammatory bowel disease (IBD)-like enteropathy. We describe an adolescent with IBD- and Behçet's-like phenotype, resulting from an intronic, loss of function mutation (c.248-7G > A) in ELF4, an X-linked transcription factor executing multiple biological functions. The mutation causes abnormal splicing and decreased mRNA expression and impairs ELF4 protein expression in the blood and colon. Functionally, the mutation results in loss of ELF4 transcriptional activity, and transcriptionally induces auto-inflammatory responses in the patient's peripheral blood mononuclear cells, which promote secretion of the pro-inflammatory cytokine interleukin-6 upon lipopolysaccharide stimulation. Single-cell transcriptional profiling of inflamed colonic biopsy specimens from the patient delineates a comprehensive landscape of mucosal innate and adaptive immune dysregulation. This analysis not only uncovers inflammatory signatures reminiscent of Crohn's disease but also demonstrates heightened angiogenic chemokine responses and enhanced chemotactic activity in innate immune cells. These results demonstrate that a new ELF4 loss-of-function intronic mutation predisposes to an intestinal autoinflammatory disorder.

Intestinal fibrosis is a significant clinical challenge in inflammatory bowel diseases, but no effective anti-fibrotic therapy is currently available. Glucagon receptor (GCGR) and glucagon-like peptide 1 receptor (GLP1R) are both peptide hormone receptors involved in energy metabolism of epithelial cells. However, their role in intestinal fibrosis and the underlying mechanisms remain largely unexplored. Herein GCGR and GLP1R were found to be reduced in the stenotic ileum of patients with Crohn’s disease as well as in the fibrotic colon of mice with chronic colitis. The downregulation of GCGR and GLP1R led to the accumulation of the metabolic byproduct lactate, resulting in histone H3K9 lactylation and exacerbated intestinal fibrosis through epithelial-to-mesenchymal transition (EMT). Dual activating GCGR and GLP1R by peptide 1907B reduced the H3K9 lactylation in epithelial cells and ameliorated intestinal fibrosis in vivo. We uncovered the role of GCGR/GLP1R in regulating EMT involved in intestinal fibrosis via histone lactylation. Simultaneously activating GCGR/GLP1R with the novel dual agonist peptide 1907B holds promise as a treatment strategy for alleviating intestinal fibrosis.

BACKGROUND/AIMS:Ustekinumab (UST) and infliximab (IFX) are both effective in the treatment of perianal fistulizing Crohn's disease (CD), but limited research has focused on comparing the efficacy of UST versus IFX in this field. This study aimed to compare the effectiveness of UST or IFX in treating perianal fistula of CD patients naive to biological agents in a real-world setting. METHODS:A retrospective cohort study included patients with perianal fistulizing CD treated with UST or IFX was conducted to evaluate the rates of luminal and perianal fistula response and remission at 6 months after treatment. RESULTS:Ninety-seven patients (49 UST and 48 IFX) were enrolled. Compared to IFX, UST exhibited significantly higher rates of treatment success (89.8% vs. 50.0%, P< 0.001) and intestinal clinical response (85.7% vs. 68.8%, P= 0.048), but no significant differences in fistula remission, fistula response, fistula closure, intestinal clinical remission, endoscopic remission and endoscopic response was observed. Furthermore, multivariate analyses demonstrated complexity of fistula was conversely associated with fistula remission between the UST and IFX groups. Finally, the rates of disease relapse and operation in the IFX group were higher as compared to the UST group during follow-up. CONCLUSIONS:UST may serve as a promising alternative to IFX for the treatment of perianal fistulizing CD.

BACKGROUND AND AIM:The global QUASAR (NCT04033445) clinical program demonstrated the efficacy and safety of guselkumab, a dual-acting interleukin-23 p19 subunit inhibitor, as induction and maintenance therapy in participants with moderate to severely active ulcerative colitis (UC). We report a subgroup analysis in East Asian participants. METHODS:The QUASAR program included two randomized, placebo-controlled, 12-week induction studies of guselkumab 200 mg (and 400 mg, Phase 2b) IV every 4 weeks (q4w) in adults with baseline modified Mayo scores of 5-9 and inadequate response/intolerance to conventional and/or advanced UC therapy. Clinical responders to guselkumab induction were re-randomized (1:1:1) at maintenance study baseline to SC guselkumab 200 mg q4w, 100 mg q8w, or placebo. Primary endpoints were clinical response (Phase 2b) or clinical remission (Phase 3) at induction Week 12 (I-12) and clinical remission at maintenance Week 44 (M-44). Subgroup analyses included participants from sites in China, Japan, Korea, and Taiwan region. RESULTS:Data were from 71 (Phase 2b) and 135 (Phase 3) East Asians in the induction studies and 106 in the maintenance study. At Week I-12, 45.5%-58.8% of guselkumab versus 25.5%-29.2% of placebo participants achieved clinical response and 16.0%-23.8% versus 4.2%-5.5%, respectively, achieved clinical remission. At Week M-44, 37.1%-46.3% of guselkumab versus 13.3% of placebo participants achieved clinical remission. The adverse event profile was generally consistent with the global QUASAR population. CONCLUSIONS:Results support the efficacy and safety of guselkumab induction and maintenance in East Asians with moderately to severely active UC, consistent with findings from the global QUASAR studies. TRIAL REGISTRATION:ClinicalTrials.gov, NCT04033445; EudraCT, 2018-004002-25.

Background Ustekinumab (UST) was approved in China for moderate-to-severe Crohn’s disease (CD) in 2020. The prevalence rates of tuberculosis and hepatitis B virus (HBV) infection are high in China, and no guideline clearly states that tuberculosis chemoprophylaxis or prophylactic anti-HBV therapy should be prescribed before UST administration. This study aimed to assess the risk of tuberculosis and HBV reactivation in CD patients with latent tuberculosis infection (LTBI) and previous HBV infection receiving UST. Methods A multicenter retrospective cohort study was carried out at 68 hospitals in China to assess 721 adult CD cases administered UST between May 1, 2020, and December 31, 2021. CD and concurrent LTBI or HBV carrier were included. Hepatitis B serology, T-SPOT.TB, and tuberculin skin tests were performed at baseline. The primary outcome was tuberculosis or HBV reactivation. Results Patients with CD-concomitant LTBI or who were HBV carriers receiving UST therapy were retrospectively enrolled from 15 hospitals in China. A total of 53 CD with LTBI patients and 17 CD with HBV carrier patients receiving UST were included. Treatment and follow-up durations were 50 ± 20 weeks and 50 ± 15 weeks in the LTBI and HBV carrier groups, respectively. A total of 25 CD patients with LTBI underwent chemoprophylaxis and 28 did not. A total of 11 HBV carriers had antiviral prophylaxis and 6 did not. No patient experienced tuberculosis or HBV reactivation or liver dysfunction during follow-up. Conclusions UST was safe for treatment of CD because no patient developed tuberculosis, persistent hepatitis, or acute liver failure during therapy, whether with a prophylactic regimen or not, based on our sample size and limited follow-up time.

PURPOSE:Behçet's disease (BD) is a complex disorder affecting multiple systems and organs, and gastrointestinal BD is poorly understood. We aimed to identify factors influencing the long-term outcomes of patients with gastrointestinal BD. METHODS:Consecutive patients with gastrointestinal BD were analyzed retrospectively. Data on the following clinical characteristics were collected: sex, age at diagnosis, symptoms, endoscopic findings, medical treatments, and surgery. Mucosal healing and surgical rates at 1, 2, and 5 years were evaluated. Log-rank test and Cox proportional hazards regression models were used to evaluate the factors affecting long-term outcomes. FINDINGS:Baseline data of 175 patients with gastrointestinal BD were included. The mean (SD) age at diagnosis was 38.3 (12.9) years. The typical clinical symptoms were oral ulcer (72.6%), abdominal pain (71.4%), and weight loss (41.1%). The most commonly involved location was the ileocecum; isolated oval ulcer was the most common ulcer type. Seventeen patients (9.7%) underwent 18 surgeries after inclusion. The cumulative surgical rates were 8.6% (n/N = 15/175), 8.6% (n/N = 15/175), and 9.1% (n/N = 16/175) in 1, 2, and 5 years, respectively. Data from 101 patients who underwent at least 2 endoscopies were included in the analysis for mucosal healing. Kaplan-Meier curve showed that the cumulative mucosal healing rates at 1, 2, and 5 years were 34.7% (n/N = 35/101), 41.6% (n/N = 42/101), and 61.4% (n/N = 62/101), respectively. We compared cumulative mucosal healing rates between 4 treatment groups, including 5-aminosalicylic acid (3% [n/N = 3/101]), mono-immunosuppressant (31.7% [n/N = 32/101]), combined therapy (36.6% [n/N = 37/101]), and escalation therapy (28.7% [n/N = 29/101]), and found that mono-immunosuppressant achieved earlier mucosal healing than combined therapy (P = 0.0008) and escalation therapy (P = 0.0008). The univariate analysis showed that moderate to severe disease activity (P = 0.013, P = 0.004), diameter of the maximal ulcer >4 cm (P = 0.002), and nonsimple esophageal involvement (P < 0.001) were risk factors, and number of ulcers between 2 and 5 was the protective factor of mucosal healing (P = 0.001). Multivariate regression analysis indicated that nonsimple esophageal involvement (P < 0.001) and the maximal ulcer >4 cm (P = 0.041) were independent risk factors of mucosal healing. IMPLICATIONS:Most patients with gastrointestinal BD need long-term treatment to achieve mucosal healing. The location and size of ulcers have a significant impact on the mucosal healing of gastrointestinal BD.

INTRODUCTION: There is a lack of reliable predictors of disease behavior progression in patients with Crohn's disease (CD). Real-time shear-wave elastography (SWE) is a novel method for evaluating tissue stiffness. However, its value for assessing CD has not yet been investigated. We aimed to explore the value of SWE and other ultrasound parameters at diagnosis in predicting CD behavior progression. METHODS: We retrospectively collected data from patients with CD with the nonstenotic nonpenetrating disease (B1 phenotype based on the Montreal classification). All patients underwent intestinal ultrasound at baseline and were followed up. The end point was defined as disease behavior progression to stricturing (B2) or penetrating (B3) disease. Cox regression analysis was performed for the association between baseline characteristics and subsequent end points. In addition, a multivariate nomogram was established to predict the risk of disease behavior progression quantitatively. RESULTS: A total of 130 patients with CD with B1 phenotype were enrolled. Twenty-seven patients (20.8%) developed B2 or B3 disease, with a median follow-up of 33 months. Multivariate analysis identified that SWE was the only independent predictor of disease behavior progression (hazard ratio 1.08, 95% confidence interval 1.03-1.12, P = 0.001). A reverse of the HR appeared at the cutoff 12.75 kPa. The nomogram incorporating SWE and other clinical characteristics showed a good prediction performance (area under the curve = 0.792). DISCUSSION: Intestinal stiffness assessed using SWE is an independent predictor of disease behavior progression in patients with CD. Patients with CD with SWE >12.75 kPa at diagnosis are prone to progress toward stricturing or penetrating diseases.

Background: Early biologic intervention after diagnosis has shown improved clinical and endoscopic outcomes in patients with Crohn’s disease (CD), while very little is known about the effectiveness of early versus late administration of Ustekinumab (UST). Objectives: We aimed to compare early versus late UST use in managing CD and identify potential predictors associated with clinical and endoscopic outcomes. Design: This was a retrospective observational study. Methods: This study included patients with CD who started UST treatment from 2020 to 2023 in our center. Clinical and endoscopic outcomes were compared between early stage (⩽24 months) and later-stage (>24 months) groups at 6 months after starting UST therapy, and clinical predictors associated with any of the outcomes were assessed by logistic regression model. Furthermore, time-to-event analyses were applied to observe CD-related prognosis during follow-up. Results: This study included 237 patients with CD, with 44.3% ( n = 105) starting UST at the early stage and 55.7% ( n = 132) at the later stage. Patients with early UST use demonstrated significantly higher rates of clinical and endoscopic remissions as compared to those with late UST use at 6 months after treatment. After adjusting for disease-related factors using multivariate logistic regression analysis, active perianal disease and severe disease were negatively associated with clinical and endoscopic remission in both early and late UST use groups. Finally, early UST administration was associated with a more favorable long-term outcome in terms of overall hospitalization and treatment escalation during follow-up. Conclusion: Starting UST therapy in the early stage of CD especially within the first 6 months was associated with high rates of clinical and endoscopic remission and a low rate of CD-related complications.

BackgroundLymphocytes play a key role in the pathogenesis of inflammatory bowel disease (IBD) and are widely explored as promising prognostic indicators. We aimed to outline the existing evidences on the capability of lymphocyte subpopulations to predict disease progression and treatment response in patients with IBD.MethodsThe protocol for this review was registered in PROSPERO (registration ID: CRD 42022364126). Systematic retrieval was conducted using PubMed, Embase, and Web of Science databases. Original articles on the prognostic value of lymphocyte subsets in IBD published up to April 8, 2023 were eligible for inclusion. The Newcastle–Ottawa Scale was used to evaluate the risk of bias.ResultsTwenty studies were ultimately included: eight evaluated the prediction of disease progression and 12 focused on the prediction of treatment response. According to the Newcastle–Ottawa Scale, three studies were of high quality, 16 were of moderate quality, and only one was of low quality. T-cell subpopulations, including CD4+ T cells, CD8+ T cells, and γδ T cells, are revealed to have prognostic capacity. Transmembrane tumor necrosis factor α-bearing lymphocytes, CD4+ T cells, CD8+ T cells, and Plasma cells are found to have the potential to predict the response to anti-TNFα agents. In contrast memory T cells, CD4+ T cells, and naïve B cells may predict the response to vedolizumab.ConclusionsThis systematic review identified several potential lymphocyte subset-related predictors. If verified in large cohort prospective studies, these findings could aid clinical decision-making.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022364126.

Endoscopy-based scoring systems, including Mayo Endoscopic Score (MES), Modified Mayo Endoscopic Score (MMES), and Degree of Ulcerative Colitis Burden of Luminal Inflammation (DUBLIN) Score, have been introduced to evaluate UC prognosis. This study aims to compare their predictive capacity for clinical outcomes in UC patients. Consecutive UC patients from a tertiary hospital were included. The primary outcome was acute severe ulcerative colitis (ASUC), and secondary outcomes were UC-related admission, medication treatment escalation, disease extension and surgery. Predictive performance was assessed using receiver operating characteristic (ROC) curves. Among 300 patients, 15.3

BACKGROUND:Disease Severity Index (DSI) provides comprehensive assessment of bowel damage (BD). AIMS:To evaluate DSI in patients with Crohn's disease (CD) at high risk of disease progression, compared to Lémann Index (LI). METHODS:Patients with CD in our center were reviewed consecutively between 2017 and 2019. DSI, LI, and complicated CD course were analyzed. RESULTS:The median LI and DSI of included 300 patients were 1.63 (IQR 1.25-3.13) and 42 (IQR 32-51), respectively. 152 patients (50.7%) experienced a complicated disease course (median 5.1 months; IQR 1.1-20.2). DSI (AUC 0.66; 95% CI 0.60-0.72) better predicted a complicated course of CD over LI (AUC 0.56; 95% CI 0.50-0.63; P = 0.007). The cumulative probability of complicated CD course in severe patients was higher than those with 'mild CD' (P < 0.001). The Cox analysis identified DSI>43 (HR 2.18; 95% CI 1.54-3.09; P < 0.001), B2/3 vs. B1 (HR 2.80; 95% CI 1.99-3.94; P < 0.001), and a higher level of CRP (HR 1.01; 95% CI 1.00-1.02; P = 0.005) as independent prognostic factors for complicated CD. However, LI was not associated with complicated CD (P = 0.164). CONCLUSIONS:Higher DSI was associated with complicated disease outcomes. DSI might play a better role than LI in identifying patients at high risks of disease progression.

Purpose: Behcet disease (BD) is a multisystemic disorder characterized by variable clinical manifes-tations that affect nearly all systems and organs. Colchicine, an alkaloid plant extract, is considered as the first-line therapy for gout, pericarditis, and familial Mediterranean fever. However, the role of colchicine in the treatment of different clinical phenotypes of BD has not been clearly described. This narrative review summarizes the clinical use of colchicine in BD. Methods: All relevant literature from 1980 to March 2021 was searched in PubMed, MEDLINE, and Cochrane Library. The Medical Subject Heading terms and related words that were searched are as follows: Behcet's disease, Behcet's syndrome, BD, colchicine, management, treatment, and therapy.Findings: BD is an autoimmune systemic vasculitis with various clinical phenotypes, with involvement of skin mucosa, joints, eyes, and gastrointestinal, vascular, and neurologic systems. Colchicine has been used for centuries, acts by binding to tubulin to prevent the mitotic process, and has anti-inflammatory, antitumor, and antifibrotic properties. Colchicine has been reported to be an effective option for the treatment of skin, mucosal, and joint involvement in patients with certain BD clinical phenotypes. Implications: Colchicine reduces the severity of certain clinical phenotypes and may improve the overall disease activity index in patients with BD. More randomized clinical trials are needed to confirm the value of colchicine in the treatment of BD, and further elucidation of the mechanisms is also needed, which may reveal new application of colchicine that has been used for centuries. (Clin Ther. 2023;45:162-176.) (c) 2023 Published by Elsevier Inc.

Introduction: Vedolizumab (VDZ) is a gut selective anti-lymphocyte trafficking (GSALT) biologic, which binds to the α4β7 integrin and reduce intestinal tissue inflammation. VDZ was approved to treat moderate-to-severe Ulcerative Colitis (UC) and Crohn’s disease (CD) patients (pts) in 2020 in China, however, the effectiveness and safety data of VDZ in Chinese inflammatory bowel disease (IBD) pts is lacking. Methods: VALUE study is a prospective, multicenter, single-armed observational study to evaluate the safety and effectiveness of VDZ in Chinese population, with a study sample size of 750 IBD pts. Two interim analyses were planned to conduct at one and 2 years after first patient enrollment. This is the first interim analysis in CD pts. A descriptive summary was provided for demographic and baseline characteristics, safety, and effectiveness. Results: Totally 62 CD pts were enrolled in this interim analysis with a median CD duration of 731 days. Among pts having Harvey-Bradshaw index (HBI) score, the mean (±SD) was 5.4 (±3.7), and 27.7% (13/47) of them had moderate-to-severe CD. Most CD pts were ileocolonic (51.6%), 11.3% (7/62) had CD-related surgery, and 50.0% (31/62) had prior biologic use (Table 1). After initiation of VDZ treatment, the HBI mean (±SD) score decreased from 5.4 (±3.7) to 3.2 (±2.3) and 3.1 (±1.3) at week 14 and 30, respectively (Figure 1). 34.5% (10/29) and 4 of 10 pts achieved clinical response at week 14 and 30, respectively; 79.3% (23/29) and 90.9% (10/11) pts achieved clinical remission at week 14 and 30, respectively (Figure 1). For pts with prior biologic use, 3 of 10 and 1 of 4 pts achieved clinical response at week 14 and 30, 9 of 10 and 3 of 4 pts achieved clinical remission at week 14 and 30, respectively. For pts without prior biologic use, 36.8% (7/19) and 3 of 6 pts achieved clinical response at week 14 and 30, 73.7% (14/19) and 7 of 7 pts achieved clinical remission at week 14 and 30, respectively (Figure 1). For moderate-to-severe CD pts (defined as baseline HBI score ＞7), 6 of 8 and 2 of 2 pts achieved clinical response at week 14 and 30, 5 of 8 and 2 of 2 pts achieved clinical remission at week 14 and 30, respectively. Most adverse events (AEs) during the treatment were mild (79.4%), 6.5% of pts had AEs leading to study discontinuation. No new safety signals were observed. Conclusion: This study showed VDZ was an effective therapy for the management of Chinese CD patients. The safety findings in this study remain in line with the known safety profile of VDZ.Figure 1.: (A) Mean HBI score at baseline, week 14 and week 30. The error bars represent one SD, (B) Clinical outcomes of CD patients after 14, 30 weeks of VDZ therapy. HBI: Harvey-Bradshaw index. a: Clinical response defined as ≥3-point decrease in the HBI score; b: Clinical remission defined as HBI score of ≤4. Table 1. - Baseline Demographic Characteristics Patient Characteristic CD (N=62) Age, years, mean (SD) 33.4 (11.45) Male, n (%) 44 (70.97%) Duration of CD, days, median 731 HBI score, mean (SD) 5.362 (3.674) Disease location of CD patients, n (%) L1 – Ileal 10 (16.13%) L2 – Colonic 10 (16.13%) L3 – Ileocolonic 32 (51.61%) L4 – Isolated upper disease 2 (3.23%) Unknown 4 (6.45%) Other 4 (6.45%) Any patient having CD-related surgery, n (%) 7 (11.29%) CD-related complications, n (%) Fistulas 11 (17.74%) Intestinal perforation 2 (3.23%) Others 5 (8.06%) Extraintestinal manifestations, n (%) Arthritis 4 (6.45%) Others 4 (6.45%) Any patient with prior medication, n (%) 47 (75.81%) 5-ASA 19 (30.65%) Steroids 6 (9.68%) IMM 5 (8.06%) Biologics 31 (50.00%) Adalimumab 2 (3.23%) Infliximab 21 (33.87%) Other TNF-α inhibitor 4 (6.45%) Interleukin 12/23 inhibitor 4 (6.45%) Other medications 17 (27.42%)

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.