Risankizumab for Ulcerative Colitis

JAMA, Journal Year: 2024, Volume and Issue: 332(11), P. 881 - 881

Published: July 22, 2024

Importance The clinical effects of risankizumab (a monoclonal antibody that selectively targets the p19 subunit IL-23) for treatment ulcerative colitis are unknown. Objective To evaluate efficacy and safety when administered as an induction a maintenance therapy patients with colitis. Design, Setting, Participants Two phase 3 randomized trials were conducted. trial was conducted at 261 centers (in 41 countries) enrolled 977 from November 5, 2020, to August 4, 2022 (final follow-up on May 16, 2023). 238 37 754 28, 2018, March 30, April 11, Eligible had moderately severely active colitis; history intolerance or inadequate response 1 more conventional therapies, advanced both types therapies; no prior exposure risankizumab. Interventions For trial, 2:1 receive 1200 mg placebo intravenously weeks 0, 8. (determined using adapted Mayo score) after intravenous 1:1:1 subcutaneous 180 360 (no longer receiving risankizumab) every 8 52 weeks. Main Outcomes Measures primary outcome remission (stool frequency score ≤1 not greater than baseline, rectal bleeding endoscopic subscore without friability) week 12 trial. Results Among 975 analyzed in (aged 42.1 [SD, 13.8] years; 586/973 [60.1%] male; 677 [69.6%] White), rates 132/650 (20.3%) 20/325 (6.2%) (adjusted between-group difference, 14.0% [95% CI, 10.0%-18.0%], P < .001). 548 40.9 14.0] 313 [57.1%] 407 [74.3%] 72/179 (40.2%) risankizumab, 70/186 (37.6%) 46/183 (25.1%) difference vs placebo, 16.3% [97.5% 6.1%-26.6%], .001; adjusted 14.2% 4.0%-24.5%], = .002). No new risks detected groups. Conclusion Relevance Compared improved Further study is needed identify benefits beyond 52-week follow-up. Trial Registration ClinicalTrials.gov Identifiers: NCT03398148 NCT03398135

Language: Английский

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Gegen Qinlian decoction ameliorates TNBS-induced ulcerative colitis by regulating Th2/Th1 and Tregs/Th17 cells balance, inhibiting NLRP3 inflammasome activation and reshaping gut microbiota

Journal of Ethnopharmacology, Journal Year: 2024, Volume and Issue: 328, P. 117956 - 117956

Published: Feb. 29, 2024

Language: Английский

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Structural characteristics of steamed Polygonatum cyrtonema polysaccharide and its bioactivity on colitis via improving the intestinal barrier and modifying the gut microbiota

Carbohydrate Polymers, Journal Year: 2023, Volume and Issue: 327, P. 121669 - 121669

Published: Dec. 7, 2023

Language: Английский

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Microbial metabolite deoxycholic acid-mediated ferroptosis exacerbates high-fat diet-induced colonic inflammation

Molecular Metabolism, Journal Year: 2024, Volume and Issue: 84, P. 101944 - 101944

Published: April 18, 2024

High-fat diet (HFD) has long been recognized as risk factors for the development and progression of ulcerative colitis (UC), but exact mechanism remained elusive. Here, HFD increased intestinal deoxycholic acid (DCA) levels, DCA further exacerbated colonic inflammation. Transcriptome analysis revealed that triggered ferroptosis pathway in mice. Mechanistically, upregulated hypoxia-inducible factor-2α (HIF-2α) divalent metal transporter-1 (DMT1) expression, causing ferrous ions accumulation epithelial cells, which was reversed by inhibitor ferrostatin-1. failed to promote intestine-specific HIF-2α-null Notably, byak-angelicin inhibited DCA-induced pro-inflammatory pro-ferroptotic effects through blocking up-regulation HIF-2α DCA. Moreover, fat intake positively correlated with disease activity UC patients consuming HFD, being more pronounced. Collectively, our findings demonstrated inflammation promoting DCA-mediated ferroptosis, providing new insights into diet-related bile dysregulation UC.

Language: Английский

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Alleviative effects of exopolysaccharides from Limosilactobacillus mucosae CCFM1273 against ulcerative colitis via modulation of gut microbiota and inhibition of Fas/Fasl and TLR4/NF-κB pathways

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 260, P. 129346 - 129346

Published: Jan. 21, 2024

Language: Английский

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PANoptosis and Autophagy-Related Molecular Signature and Immune Landscape in Ulcerative Colitis: Integrated Analysis and Experimental Validation

Journal of Inflammation Research, Journal Year: 2024, Volume and Issue: Volume 17, P. 3225 - 3245

Published: May 1, 2024

Background: Ulcerative colitis (UC) is an autoimmune inflammatory disorder of the gastrointestinal tract. Programmed cell death (PCD), including PANoptosis and autophagy, plays roles in inflammation immunity. This study aimed to investigate molecular signature immune landscape PANoptosis- autophagy-related differentially expressed genes (DEGs) UC. Methods: Analyzing UC dataset GSE206285 yielded DEGs. Differentially were identified using DEGs relevant gene collections. Functional pathway enrichment analyses conducted. A protein-protein interaction (PPI) network was established identify hub genes. TRRUST database predicted transcription factors (TFs), pivotal miRNAs, drugs interacting with Immune infiltration analysis, UC-associated single-cell sequencing data construction a competing endogenous RNA (ceRNA) for Machine learning key candidate genes, evaluated diagnostic value via receiver operating characteristic (ROC) curves. mice model verified expression Results: Identifying ten PANoptosis-related four associated them chemotaxis, wound healing positive MAPK cascade regulation. analysis revealed increased immunocyte patients, closely linked various infiltrations. five TIMP1, TIMP2, TIMP3, IL6, CCL2, strong performance. At level, these exhibited high fibroblasts (IAFs). They showed significant differences colon mucosa both patients model. Conclusion: validated novel signatures autophagy UC, potentially influencing dysregulation healing, thus opening avenues future research therapeutic interventions. Keywords: ulcerative colitis, PANoptosis, infiltration, fibroblasts, bioinformatics

Language: Английский

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Harms with placebo in trials of biological therapies and small molecules as maintenance therapy in inflammatory bowel disease: a systematic review and meta-analysis

˜The œLancet. Gastroenterology & hepatology, Journal Year: 2024, Volume and Issue: 9(11), P. 1030 - 1040

Published: Sept. 20, 2024

Randomised placebo-controlled trials for the induction of inflammatory bowel disease (IBD) remission involve potential harms to those receiving placebo. Whether these are also apparent with placebo during maintenance in IBD is unclear. We aimed examine associated licensed biologics and small molecules ulcerative colitis luminal Crohn's a meta-analysis.

Language: Английский

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Risankizumab Efficacy and Safety Based on Prior Inadequate Response or Intolerance to Advanced Therapy: Post Hoc Analysis of the INSPIRE and COMMAND Phase 3 Studies

Journal of Crohn s and Colitis, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 10, 2025

Abstract Background and Aims Treating ulcerative colitis (UC) in patients with prior advanced therapy (AT) exposure may be challenging. We report the efficacy safety of risankizumab, a monoclonal interleukin 23p19 antibody, UC inadequate response or intolerance to AT (AT-IR). Methods In 12-week phase 3 INSPIRE induction study, were randomized intravenous risankizumab 1200 mg placebo. Clinical responders subcutaneous 180 mg, 360 placebo (risankizumab withdrawal) 52-week COMMAND maintenance study. This post hoc analysis assessed outcomes by AT-IR status, number, mechanism action. included biologics, Janus kinase inhibitors, sphingosine-1-phosphate receptor modulators. Results Efficacy analyses 472 Non-AT-IR 503 (induction), 137 411 (maintenance). More achieved clinical remission per Adapted Mayo score versus at week 12 (Non-AT-IR, 29.7% 8.4%, nominal P < .0001; AT-IR, 11.4% 4.3%, = .0083); consistent (withdrawal) 52 (NonAT-IR, 50.9% 61.7% 31.1%, .057 .0033, respectively; 36.6% 29.5% 23.2%, .0159 .2334, respectively). Risankizumab had increased over placebo, regardless number action, higher rates for NonAT-IR compared AT-IR. Safety results generally comparable both maintenance. Conclusion was effective well tolerated, status.

Language: Английский

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Advancing Inflammatory Bowel Disease Treatment by Targeting the Innate Immune System and Precision Drug Delivery

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(2), P. 575 - 575

Published: Jan. 11, 2025

Inflammatory bowel disease (IBD), encompassing Crohn's and ulcerative colitis, involves chronic inflammation of the gastrointestinal tract. Current immune-modulating therapies are insufficient for 30-50% patients or cause significant side effects, emphasizing need new treatments. Targeting innate immune system enhancing drug delivery to inflamed gut regions promising strategies. Neutrophils play a central role in IBD by releasing reactive oxygen species (ROS) neutrophil extracellular traps (NETs) -DNA-based structures with cytotoxic proteins-that contribute mucosal damage inflammation. Recent studies linking ROS production, DNA repair, NET formation have identified NETs as potential therapeutic targets, preclinical models showing positive outcomes from inhibition. Innovative oral systems designed target directly-without systemic absorption-could improve treatment precision reduce effects. Advanced formulations utilize properties such particle size, surface modifications, ROS-triggered release selectively distal ileum colon. A dual strategy that combines deeper understanding pathophysiology identify inflammation-related targets advanced may offer promise. For instance, pairing inhibition ROS-responsive nanocarriers could enhance efficacy, though further research is needed. This synergistic approach has greatly patients.

Language: Английский

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Specialized pro-resolving lipid mediators in gut immunophysiology: from dietary precursors to inflammation resolution

Current Opinion in Clinical Nutrition & Metabolic Care, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 14, 2025

Purpose of review This aims to examine recent research on the role specialized pro-resolving mediators (SPMs) in regulation gut immunophysiology. Recent findings Inflammatory bowel disease (IBD) is characterized by chronic inflammation gastrointestinal tract, driven disruptions intestinal barrier and an imbalance between host immune system microbiota. Dietary polyunsaturated fatty acids (PUFAs), especially ω-3 ω-6, are key regulators responses help maintain integrity barrier. These PUFAs serve as precursors SPMs, lipid that play a critical resolving inflammation. SPMs actively reprogram cells, promoting clearance cellular debris, reducing cytokine production, restoring tissue homeostasis without suppressing response. Emerging evidence indicates gut, strengthen function, modulate colitis colon cancer, influence microbiota composition. Summary The strongly supports central maintaining health organ function following inflammatory challenges. highlights potential therapeutic approaches target these pathways for both prevention treatment gut-related conditions.

Language: Английский

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