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Cornet N, Aboubakr A, Ahmed W, Battat R. Combined Advanced Targeted Therapy in Inflammatory Bowel Diseases: An Extensive Update. Inflamm Bowel Dis 2025; 31:1138-1144. [PMID: 39207309 DOI: 10.1093/ibd/izae189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Indexed: 09/04/2024]
Abstract
Lay Summary
This article discusses the rationale for and the current data on the efficacy and safety of combined advanced targeted therapy (CATT) for the treatment of moderate-to-severe inflammatory bowel disease.
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Affiliation(s)
- Nicole Cornet
- Department of Medicine, NewYork Presbyterian-Weill Cornell Medicine, New York, NY, USA
| | - Aiya Aboubakr
- Division of Gastroenterology, NewYork Presbyterian-Weill Cornell Medicine, New York, NY, USA
| | - Waseem Ahmed
- Department of Gastroenterology, University of Colorado Crohn's and Colitis Center, Aurora, CO, USA
| | - Robert Battat
- Department of Gastroenterology and Hepatology, Center Hospitalier de l' Université de Montreal, Montreal, QC, Canada
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Kruger AJ, Dormont F, Capit N, Schilsky S, Roberts A, Lin Y, Badalamenti S, Wiekowski M, Bewtra M, Colombel JF. Biologic Switch Timing and Risk of Infection in Patients With Ulcerative Colitis/Crohn's Disease: A Retrospective Study. Clin Gastroenterol Hepatol 2025:S1542-3565(25)00245-9. [PMID: 40204205 DOI: 10.1016/j.cgh.2025.01.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 12/20/2024] [Accepted: 01/22/2025] [Indexed: 04/11/2025]
Abstract
BACKGROUND & AIMS There is limited evidence on real-world patterns and safety of biologic switch timing in patients with ulcerative colitis (UC)/Crohn's disease (CD). This study investigated biologic therapy switch occurrence in real-world practice and compared the risk of any infection and serious infection between patients with overlapping (OS) vs non-overlapping switches (NOS). METHODS This retrospective observational study identified patients with UC/CD initiating biologic therapy between September 1, 2017, and August 31, 2022, in Optum's de-identified Clinformatics Data Mart Database. Crude incidence rates (IRs) per 1000 person-years (PYs) and timing of switch were assessed. Biologic switch events were categorized as OS (switch to another biologic within ≤5 half-lives after discontinuation of initial biologic) or NOS (switch to another biologic >5 half-lives after discontinuation of initial biologic). Inverse probability of treatment weighted Cox proportional hazards modeling estimated adjusted hazard ratios (aHRs) of any infection and serious infection associated with switch timing. RESULTS Among 11,992 adult patients newly initiating a biologic therapy for UC/CD, 1293 patients underwent a biologic switch, 64.2% of which were considered an OS. Adjusted IRs per 1000 PYs, for any infection, were comparable across switching groups. No significant differences in the aHRs of infections were found between OS and NOS (any infection: aHR, 1.40; P = .17; serious infection: aHR, 0.95; P = .93). CONCLUSION OSs were common and not associated with an increased risk of serious infection vs non-overlapping biologics. Shortened washout periods may pose minimal safety risks to patients while improving UC/CD therapy management and improving trial recruitment.
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Affiliation(s)
- Annie J Kruger
- Immunology and Inflammation, Sanofi, Cambridge, Massachusetts.
| | | | | | | | | | - Yong Lin
- Inflammation and Immunology, Sanofi, Bridgewater, New Jersey
| | | | - Maria Wiekowski
- Inflammation and Immunology, Sanofi, Bridgewater, New Jersey
| | - Meenakshi Bewtra
- Department of Medicine and Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Jean-Frederic Colombel
- Department of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
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Zhao L, Jiang T, Zhang Y, Shen Z. Epimedium polysaccharides ameliorate ulcerative colitis by inhibiting oxidative stress and regulating autophagy. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2025; 105:2655-2670. [PMID: 39540346 DOI: 10.1002/jsfa.14037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 10/09/2024] [Accepted: 11/01/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Epimedium polysaccharide (EPS) is a bioactive compound derived from the traditional Chinese herb Epimedium brevicornum. The objective of this study was to investigate the protective effects of EPS on ulcerative colitis (UC) and to elucidate the underlying mechanisms involved. RESULTS The findings showed that EPS treatment mitigated UC symptoms, including weight loss, anal bleeding, elevated disease activity index (DAI), and colon shortening. Hematoxylin and eosin (H&E) and Alcian blue-periodic acid-Schiff (AB-PAS) staining demonstrated that EPS alleviated histopathological damage and improved the integrity of the colonic mucosa. Mechanistically, EPS was found to substantially decrease inflammation by inhibiting the Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) signaling pathway and to alleviate oxidative stress through modulation of the Kelch-like ECH-associated protein 1/nuclear factor erythroid-derived 2-like 2 (Keap1/Nrf2) pathway. Notably, EPS failed to exert protective effects against dextran sulfate sodium (DSS)-induced UC in Nrf2-knockout (Nrf2-/-) mice. Additionally, Western blotting and immunohistochemical analysis demonstrated that EPS facilitated autophagy via the adenosine monophosphate-dependent protein kinase/mammalian target of rapamycin (AMPK/mTOR) pathway. In vitro experiments revealed that EPS effectively suppressed lipopolysaccharide (LPS)-mediated cellular damage and oxidative stress by regulating Keap1/Nrf2 pathway. Transcriptomic analysis of LPS-treated Caco-2 cells following EPS treatment revealed a significant up-regulation of Nrf2 expression. CONCLUSION In conclusion, the findings of this study suggest that EPS exerts protective effects against DSS-induced UC through the inhibition of the TLR4/NF-κB signaling pathway, regulation of the Keap1/Nrf2 pathway, and promotion of autophagy via the AMPK/mTOR pathway. Consequently, EPS may represent a potential therapeutic target for the treatment of UC. © 2024 Society of Chemical Industry.
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Affiliation(s)
- Linxian Zhao
- Department of Gastrointestinal, Colorectal, and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Tao Jiang
- Department of Vascular Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yuxin Zhang
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Zhen Shen
- Department of Gastrointestinal, Colorectal, and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
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Altieri G, Zilli A, Parigi TL, Allocca M, Furfaro F, Fiorino G, Cicerone C, Peyrin-Biroulet L, Danese S, D’Amico F. Dual Therapy in Inflammatory Bowel Disease. Biomolecules 2025; 15:222. [PMID: 40001525 PMCID: PMC11853240 DOI: 10.3390/biom15020222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 01/29/2025] [Accepted: 02/01/2025] [Indexed: 02/27/2025] Open
Abstract
Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic and complex autoimmune conditions. Despite the advancements in biologics and small molecules, the therapeutic ceiling persists, posing significant treatment challenges and contributing to the concept of difficult-to-treat IBD. Dual-targeted therapy (DTT), combining two biologic agents or biologics with small molecules, has emerged as a novel approach to address this unmet need by targeting multiple inflammatory pathways simultaneously. Evidence suggests that DTT holds promise in improving clinical and endoscopic outcomes, especially in patients with refractory disease or extraintestinal manifestations. Safety data, while consistent with monotherapy profiles, highlight the importance of vigilant monitoring for infections and other adverse events. Continued research and high-quality trials are crucial to defining optimal DTT regimens and broadening its clinical applicability. This review explores the efficacy and safety of DTT in IBD, reporting data from clinical trials, systematic reviews, and real-world studies.
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Affiliation(s)
- Gabriele Altieri
- Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy; (G.A.)
- Faculty of Medicine and Surgery, Vita Salute San Raffaele University, 20132 Milan, Italy
| | - Alessandra Zilli
- Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy; (G.A.)
| | - Tommaso Lorenzo Parigi
- Faculty of Medicine and Surgery, Vita Salute San Raffaele University, 20132 Milan, Italy
| | - Mariangela Allocca
- Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy; (G.A.)
| | - Federica Furfaro
- Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy; (G.A.)
| | - Gionata Fiorino
- Gastroenterology and Digestive Endoscopy, San Camillo-Forlanini Hospital, 00152 Rome, Italy
| | - Clelia Cicerone
- Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy; (G.A.)
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, INFINY Institute, INSERM NGERE, CHRU de Nancy, Université de Lorraine, F-54500 Vandœuvre-lès-Nancy, France
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy; (G.A.)
- Faculty of Medicine and Surgery, Vita Salute San Raffaele University, 20132 Milan, Italy
| | - Ferdinando D’Amico
- Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy; (G.A.)
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Wang S, Wang P, Wang D, Shen S, Wang S, Li Y, Chen H. Postbiotics in inflammatory bowel disease: efficacy, mechanism, and therapeutic implications. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2025; 105:721-734. [PMID: 39007163 DOI: 10.1002/jsfa.13721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 05/29/2024] [Accepted: 06/19/2024] [Indexed: 07/16/2024]
Abstract
Inflammatory bowel disease (IBD) is one of the most challenging diseases in the 21st century, and more than 10 million people around the world suffer from IBD. Because of the limitations and adverse effects associated with conventional IBD therapies, there has been increased scientific interest in microbial-derived biomolecules, known as postbiotics. Postbiotics are defined as the preparation of inanimate microorganisms and/or their components that confer a health benefit on the host, comprising inactivated microbial cells, cell fractions, metabolites, etc. Postbiotics have shown potential in enhancing IBD treatment by reducing inflammation, modulating the immune system, stabilizing intestinal flora and maintaining the integrity of intestinal barriers. Consequently, they are considered promising adjunctive therapies for IBD. Recent studies indicate that postbiotics offer distinctive advantages, including spanning clinical (safe origin), technological (easy for storage and transportation) and economic (reduced production costs) dimensions, rendering them suitable for widespread applications in functional food/pharmaceutical. This review offers a comprehensive overview of the definition, classification and applications of postbiotics, with an emphasis on their biological activity in both the prevention and treatment of IBD. © 2024 Society of Chemical Industry.
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Affiliation(s)
- Shuxin Wang
- Marine College, Shandong University, Weihai, China
| | - Pu Wang
- Marine College, Shandong University, Weihai, China
| | - Donghui Wang
- Marine College, Shandong University, Weihai, China
| | | | - Shiqi Wang
- Marine College, Shandong University, Weihai, China
| | - Yuanyuan Li
- Department of Food Science, Cornell University, Ithaca, NY, USA
| | - Hao Chen
- Marine College, Shandong University, Weihai, China
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Wang J, Lv X, Li Y, Wu H, Chen M, Yu H, Wu J, Li C, Xiong W. A ROS-responsive hydrogel that targets inflamed mucosa to relieve ulcerative colitis by reversing intestinal mucosal barrier loss. J Control Release 2025; 377:606-618. [PMID: 39608456 DOI: 10.1016/j.jconrel.2024.11.065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 11/22/2024] [Accepted: 11/25/2024] [Indexed: 11/30/2024]
Abstract
Intestinal mucosal barrier loss is responsible for the chronic and recurrent ulcerative colitis. Myosin light chain kinase (MLCK) is a potential therapeutic target of the intestinal mucosal barrier dysfunction. Here, we developed a reactive oxygen species (ROS)-sensitive hydrogel (ATG-CS-Gel) derived from a diselenide-bridged arctigenin (ATG) and chitosan (CS) conjugate, with the aims of targeting to inflamed mucosa and modulating MLCK. Our results demonstrated that ATG-CS-Gel achieved ROS-responsive release and significantly inhibited ROS production and mitochondrial depolarization in the Caco-2 and HT-29/MTX-E12 cells under H2O2-induced stress conditions. Compared with normal tissues, orally-administrated ATG-CS-Gel preferentially adhered to the inflamed mucosa for 24 h, which was attributed to the adhesion between CS and mucin. Therapeutically, ATG-CS-Gel reduced inflammatory symptoms, accelerated intestinal mucosal healing, scavenged excessive ROS, reshaped intestinal flora, and eventually achieved much better therapeutic efficacy in DSS-induced colitis mice when compared to 5-aminosalicylic acid. Moreover, ATG-CS-Gel was demonstrated to reverse intestinal mucosal barrier loss by blocking MLCK activation and maintaining tight junction expression. In summary, this study highlights the potential of MLCK modulation in the restoration of intestinal mucosal barrier using ATG-CS-Gel. The development of ATG-CS-Gel represents a novel and promising strategy for the treatment of ulcerative colitis.
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Affiliation(s)
- Jianwei Wang
- School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China
| | - Xiaojia Lv
- School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China
| | - Ying Li
- School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China
| | - Haiqiang Wu
- School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China
| | - Meiwan Chen
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao
| | - Hua Yu
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao
| | - Jianwei Wu
- Division of Gastroenterology, Baoan People's Hospital of Shenzhen (Group), Shenzhen 518055, China
| | - Chenyang Li
- School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China.
| | - Wei Xiong
- School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China.
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Jin X, Sun K, Wang L, Shen H, Ma D, Shen T, Chen C, Li L. Efficacy and safety of dual-targeted therapy for inflammatory bowel disease: a retrospective multicenter study in China. Therap Adv Gastroenterol 2025; 18:17562848241307598. [PMID: 39758966 PMCID: PMC11696958 DOI: 10.1177/17562848241307598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 11/29/2024] [Indexed: 01/07/2025] Open
Abstract
Background Treatment options for patients with refractory inflammatory bowel disease (IBD) or concomitant IBD and extraintestinal manifestations (EIM) are often limited. Objective This study aimed to examine the efficacy and safety of combining biologics or small molecules in patients with refractory IBD, active EIM, or active immune-mediated inflammatory disease (IMID). Design This was a retrospective and multicenter study. Methods We retrospectively collected demographics and disease characteristics from 47 patients with IBD who received dual-targeted therapy in 3 hospitals from January 2022 to June 2024. The primary endpoint was clinical remission based on the Harvey-Bradshaw index or patient-reported outcome 2 after at least 4 months of combination therapy. The secondary endpoints included clinical response, endoscopic response, and endoscopic remission, as well as all adverse events that occurred within the period of combination therapy. Results In total, 47 IBD patients including 37 with refractory IBD, 5 with active EIM, and 5 with active IMID received dual-targeted therapy, of which 37 achieved clinical response (78.7%) and 27 achieved clinical remission (57.4%) at a median follow-up time of 13.0 months. Among these 47 patients, 29 patients underwent endoscopic follow-up, of which 15 (51.7%) achieved endoscopic response and 8 (27.6%) achieved endoscopic remission at a median follow-up time of 9.0 months. Mild and moderate adverse events were reported in 17 (36.2%) patients within the period of combination therapy, and serious adverse events requiring hospitalization occurred in 1 patient (2.1%). Conclusion The combination therapy of biologics and small molecules for refractory IBD or those with concomitant EIM/IMID is effective and safe.
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Affiliation(s)
- Xiuxiu Jin
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Kefang Sun
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Liying Wang
- Department of Gastroenterology, Shangyu People’s Hospital of Shaoxing, Shangyu, Zhejiang, China
| | - Haiyan Shen
- Department of Gastroenterology, The Second Hospital of Jiaxing, Jiaxing, Zhejiang, China
| | - Dan Ma
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Tejia Shen
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Chunxiao Chen
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, China
| | - Lan Li
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, China
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Bhaskar S, Makovich Z, Mhaskar R, Coughlin E, Seminerio-Diehl J. Exploring Dual-Targeted Therapy in the Management of Moderate to Severe Inflammatory Bowel Disease: A Retrospective Study. CROHN'S & COLITIS 360 2025; 7:otae057. [PMID: 39877297 PMCID: PMC11772558 DOI: 10.1093/crocol/otae057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Indexed: 01/31/2025] Open
Abstract
Background Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), often results in significant morbidity among patients with moderate to severe forms. While biologics and small molecules are effective in inducing remission, many patients experience refractory disease or extraintestinal manifestations. This study assesses the safety and efficacy of dual-targeted therapy in IBD patients treated at the Inflammatory Bowel Disease Center. Methods This retrospective cohort study examined 79 patients with UC or CD who received dual-targeted therapy at the University from October 2018 to August 2023. Data collected included demographics, disease characteristics, previous treatments, and clinical outcomes. Primary outcomes were endoscopic, radiographic, and patient-reported clinical improvements, with secondary outcomes focusing on safety profiles. Results Among the 79 patients (42 UC, 37 CD), 97 dual-targeted therapy cases were analyzed, primarily involving a biologic combined with a JAK inhibitor (90.7%). The median therapy duration was 39.1 weeks. Endoscopic improvement occurred in 69% of matched samples, with significant differences between pre- and postdual-targeted therapy Mayo scores for UC (P = .002) and Simple Endoscopic Score for CD (SES-CD) scores for CD (P = .018). The median pre- and postdual-targeted therapy Mayo scores across matched samples were 3 (range 1-3) and 1 (range 0-3), respectively, and for SES-CD scores were 12 (range 0-36) and 4 (range 0-20), respectively. Clinical improvement was reported by 73.2% of patients, with notable reductions in ESR (median 19 [range 2-124] mm/h to 9 [range 0-116] mm/h, P = .006), CRP (median 8.0 [range 0.2-78.5] mg/L to 3.0 [range 0.2-68.2] mg/L, P < .001), and albumin levels (4.0 [range 2.2-4.9] mg/dL to 4.2 [range 3.4-5.2], P < .001). Non-obesity was associated with both more endoscopic improvement (P = .002) and clinical improvement (P = .007). Adverse events occurred in 37 cases, predominantly upper respiratory tract infections and dermatologic issues, with no thromboembolic events reported. Conclusions Dual-targeted therapy demonstrated efficacy in improving clinical and endoscopic outcomes in patients with severe, refractory IBD and exhibited an acceptable safety profile. Despite the promising results, further research is needed to confirm these findings and determine optimal therapy combinations.
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Affiliation(s)
- Sonya Bhaskar
- Division of Digestive Diseases and Nutrition, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Zachary Makovich
- Division of Digestive Diseases and Nutrition, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Rahul Mhaskar
- Division of Digestive Diseases and Nutrition, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Emily Coughlin
- Division of Digestive Diseases and Nutrition, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Jennifer Seminerio-Diehl
- Division of Digestive Diseases and Nutrition, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
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Zeng C, Zhu Q, Peng W, Huang C, Chen H, Huang H, Zhou Y, Zhao C. The protective effect of amitriptyline on experimental colitis through inhibiting TLR-4/MD-2 signaling pathway. J Pharmacol Exp Ther 2025; 392:100024. [PMID: 39892990 DOI: 10.1124/jpet.124.002207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 08/23/2024] [Accepted: 08/26/2024] [Indexed: 10/10/2024] Open
Abstract
Amitriptyline, a pleiotropic tricyclic antidepressant, possesses antioxidant and anti-inflammatory properties. Despite its diverse benefits, the specific effects of amitriptyline on inflammatory bowel disease (IBD) are not yet well defined. To explore this, we used a dextran sulfate sodium (DSS)-induced colitis model to examine the anti-inflammatory effects of amitriptyline and the underlying mechanisms by which it operates. Our research revealed that amitriptyline is effective in alleviating several pathological manifestations associated with colitis. This includes improving body weight retention, reducing disease activity index, lessening of colon length shortening, and repairing of colonic mucosal damage. Treatment with amitriptyline significantly protected mucosal injury by preserving the population of goblet cells and increasing the expression of tight junction proteins. Furthermore, we observed that amitriptyline effectively countered immune cell infiltration, specifically neutrophils and macrophages, while simultaneously lowering the levels of inflammatory cytokines such as tumor necrosis factor α, interleukin (IL)-1β, and IL-6. Additionally, RNA sequencing analysis pointed to the potential involvement of the Toll-like receptor (TLR) pathway in the anticolitic effects induced by amitriptyline. Subsequent Western blot analysis indicated that amitriptyline significantly inhibited the TLR-4-mediated nuclear factor (NF)-κB signaling pathway. To bolster our findings, in vitro studies demonstrated that amitriptyline downregulated the TLR-4/NF-κB/mitogen-activated protein kinase signaling cascades in mouse macrophages stimulated with lipopolysaccharide. Further molecular investigations revealed that amitriptyline was able to suppress the elevated expression of myeloid differentiation factor 2 that lipopolysaccharide stimulation typically induces. In summary, our findings suggest that amitriptyline effectively mitigates DSS-induced colitis in mice through the inhibition of TLR-4/myeloid differentiation 2 pathway signaling, indicating its potential repurposing for IBD treatment. SIGNIFICANCE STATEMENT: The potential of using amitriptyline in treating inflammatory bowel disease appears promising, leveraging its established safety and dosing profile as an antidepressant. The study results show that amitriptyline can alleviate pathological symptoms, inflammation, and intestinal mucosal damage in mice with colitis induced by DSS. The protective effect observed appears to be linked to the inhibition of TLR-4/myeloid differentiation 2 signaling pathway. By exploring novel applications for existing medications, we can optimize amitriptyline's efficacy and broaden its impact in both medical and commercial contexts.
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Affiliation(s)
- Chengcheng Zeng
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medical, South China University of Technology, Guangzhou, Guangdong, China; Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, China
| | - Qingqing Zhu
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medical, South China University of Technology, Guangzhou, Guangdong, China; Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, China
| | - Wu Peng
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medical, South China University of Technology, Guangzhou, Guangdong, China; Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, China
| | - Chen Huang
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medical, South China University of Technology, Guangzhou, Guangdong, China; Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, China
| | - Huiting Chen
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medical, South China University of Technology, Guangzhou, Guangdong, China; Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, China
| | - Hongli Huang
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medical, South China University of Technology, Guangzhou, Guangdong, China; Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, China
| | - Yongjian Zhou
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medical, South China University of Technology, Guangzhou, Guangdong, China; Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, China
| | - Chong Zhao
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medical, South China University of Technology, Guangzhou, Guangdong, China; Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, China.
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Harwansh RK, Bhati H, Deshmukh R, Rahman MA. Preparation, Characterization, and In Vitro Evaluation of Chlorogenic Acid Loaded Hydrogel Beads for the Management of Ulcerative Colitis. Assay Drug Dev Technol 2025; 23:29-43. [PMID: 39630502 DOI: 10.1089/adt.2024.072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2025] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory colon disorder. Several modern medicines have been used for UC treatment but are associated with side effects. Hence, herbal medicine-inspired lead molecules are promising for managing UC. Chlorogenic acid (CGA), an herbal bioactive, has been reported for anti-inflammatory, anticancer, antioxidant, and immunomodulatory activity. The current study aimed to develop enteric-coated mucoadhesive beads of CGA for colon targeting. CGA-loaded beads were prepared using chitosan and carrageenan as polymers through an ionic gelation technique. Furthermore, beads were coated with Eudragit S-100. The formulations were characterized by particle size analyzer, ultraviolet (UV)-spectroscopy, Fourier transform infrared spectroscopy (FTIR), scanning electron microscope (SEM), and in vitro drug release study. The optimized formulation (CGA-F2) showed particle size (440.6 ± 6.1 μm), zeta potential (-31.12 ± 2.16 mV), entrapment efficiency (83.56 ± 5.46), %yield (86.87 ± 4.19), and drug loading (1.14 ± 0.09). SEM indicated that the morphologies of CGA-F2 were spherical and ellipsoidal. The FTIR study confirmed the compatibility of the drug with polymers used in the formulations. CGA-F2 exhibited mucoadhesive efficiency (94.33 ± 2.1%) and swelling index (0.98 ± 0.03) at simulated colonic fluid (SCF) pH 7.4 (***p < 0.001) significantly. In an in vitro drug release study, CGA-F2 (95.07 ± 3.85%) showed a sustained drug release profile in SCF (pH 7.4) at 37 ± 0.5°C for 24 h. Optimized formulation exhibited drug release in a sustained manner for 24 h, which may be due to the effect of mucoadhesive and enteric coating polymer. Hence, CGA-loaded beads would be promising for treating the UC.
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Affiliation(s)
- Ranjit K Harwansh
- Institute of Pharmaceutical Research, GLA University, Mathura, India
| | - Hemant Bhati
- Institute of Pharmaceutical Research, GLA University, Mathura, India
| | - Rohitas Deshmukh
- Institute of Pharmaceutical Research, GLA University, Mathura, India
| | - Mohammad Akhlaquer Rahman
- Department of Pharmaceutics and Industrial Pharmacy, College of Pharmacy, Taif University, Taif, Kingdom of Saudi Arabia
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11
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Solitano V, Yuan Y, Singh S, Ma C, Nardone OM, Fiorino G, Acosta Felquer ML, Barra L, D'Agostino MA, Pope J, Peyrin-Biroulet L, Danese S, Jairath V. Efficacy and safety of Advanced Combination Treatment in immune-mediated inflammatory disease: A systematic review and meta-analysis of randomized controlled trials. J Autoimmun 2024; 149:103331. [PMID: 39509741 DOI: 10.1016/j.jaut.2024.103331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 09/30/2024] [Accepted: 10/27/2024] [Indexed: 11/15/2024]
Abstract
OBJECTIVES Advanced combination treatment (ACT), defined as a combination of at least 2 biologic agents, a biologic agent and an oral small molecule, 2 oral small molecules drug with different mechanisms of action is a proposed strategy to improve outcomes in patients with immune-mediated inflammatory disease (IMID). We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing ACT with monotherapy in patients with select IMIDs. METHODS Through a systematic literature search, we identified 10 RCTs (n = 1154) comparing ACT with single agent therapy (monotherapy). The primary outcome was induction of clinical remission. Secondary outcomes were adverse events, serious adverse events, infections, and serious infections. We performed random-effects meta-analysis and used GRADE to appraise certainty of evidence. RESULTS Eight out of 10 trials investigated an anti-TNF-α drug (e.g., etanercept, infliximab, golimumab, certolizumab) combined with another biologic (e.g anti-IL-23, anti-integrin, anti-IL-1) or an oral small molecule. There was no significant difference in the likelihood of achieving clinical remission with ACT vs. monotherapy in patients with rheumatoid arthritis (n = 7 RCTs) (RR, 1.75 [95 % CI 0.60-5.13]; moderate heterogeneity (I2 = 33 %)] and systemic lupus erythematosus (n = 1) (RR, 1.20 [0.53-2.72]) (GRADE; low certainty evidence). Patients with rheumatoid arthritis in the ACT arm were more likely to experience adverse events (RR, 1.07 [1.01-1.12]) compared to monotherapy. ACT led to higher rates of induction of clinical remission in patients with IBD (n = 2 RCTs) (RR, 1.68 [1.15-2.46]) with minimal heterogeneity (I2 = 15 %) (GRADE; low certainty evidence), and no differences in the likelihood of adverse events (RR 0.92 [0.80-1.05]). There were no differences in the risk of infections or serious infections in patients treated with ACT or monotherapy with rheumatological disease or IBD. CONCLUSIONS ACT did not offer clinical benefit in patients with rheumatological IMIDs and resulted in higher rate adverse events in rheumatoid arthritis. ACT may offer clinical benefit without a clear safety signal in patients with IBD, but further trials are warranted. The variability in ACT regimens across studies limits the generalizability of these findings.
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Affiliation(s)
- Virginia Solitano
- Department of Medicine, Division of Gastroenterology, Western University, London, Ontario, Canada; Gastroenterology and Endoscopy, IRCCS Hospital San Raffaele and University Vita-Salute San Raffaele, Milan, Italy
| | - Yuhong Yuan
- Department of Medicine, Division of Gastroenterology, Western University, London, Ontario, Canada; Lawson Health Research Institute, London Health Science Center, London, Ontario, Canada
| | - Siddharth Singh
- Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Christopher Ma
- Division of Gastroenterology & Hepatology, University of Calgary, Calgary, Alberta, Canada; Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
| | - Olga Maria Nardone
- Gastroenterology, Department of Public Health, University Federico II of Naples, Naples, Italy
| | - Gionata Fiorino
- Gastroenterology and Endoscopy, IRCCS Hospital San Raffaele and University Vita-Salute San Raffaele, Milan, Italy; IBD Unit, Department of Gastroenterology & Digestive Endoscopy, San Camillo-Forlanini Hospital, 00152, Rome, Italy
| | - Maria Laura Acosta Felquer
- Rheumatology Unit, Internal Medical Services, Hospital Italiano de Buenos Aires, Argentina and Instituto Universitario, Peron 4190 (C1199ABB), CABA, Argentina
| | - Lillian Barra
- Schulich School of Medicine, University of Western Ontario, London, Ontario, Canada; Department of Medicine, Division of Rheumatology, Western University, London, ON, Canada
| | - Maria-Antonietta D'Agostino
- Department of Rheumatology, Fondazione Policlinico Universitario A. Gemelli, IRCSS, Catholic University of Sacred Heart, Rome, Italy
| | - Janet Pope
- Department of Medicine, Division of Rheumatology, Western University, London, ON, Canada
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Nancy University Hospital, F-54500, Vandœuvre-lès-Nancy, France; INFINY Institute, Nancy University Hospital, F-54500, Vandœuvre-lès-Nancy, France; Groupe Hospitalier Privé Ambroise Paré - Hartmann Paris IBD Center, 92200, Neuilly sur Seine, France
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Hospital San Raffaele and University Vita-Salute San Raffaele, Milan, Italy
| | - Vipul Jairath
- Department of Medicine, Division of Gastroenterology, Western University, London, Ontario, Canada; Department of Epidemiology & Biostatistics, Western University, London, Ontario, Canada.
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12
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Zhang ZN, Sang LX. Dual-targeted treatment for inflammatory bowel disease: Whether fecal microbiota transplantation can be an important part of it. World J Gastroenterol 2024; 30:4025-4030. [PMID: 39351254 PMCID: PMC11439114 DOI: 10.3748/wjg.v30.i36.4025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 08/24/2024] [Accepted: 09/06/2024] [Indexed: 09/20/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic gastrointestinal inflammatory disease. With the emergence of biologics and other therapeutic methods, two biologics or one biologic combined with a novel small-molecule drug has been proposed in recent years to treat IBD. Although treatment strategies for IBD are being optimized, their efficacy and risks still warrant further consideration. This editorial explores the current risks associated with dual-targeted treatment for IBD and the great potential that fecal microbiota transplantation (FMT) may have for use in combination therapy for IBD. We are focused on addressing refractory IBD or biologically resistant IBD based on currently available dual-targeted treatment by incorporating FMT as part of this dual-targeted treatment. In this new therapy regimen, FMT represents a promising combination therapy.
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Affiliation(s)
- Zi-Ning Zhang
- Department of Gastroenterology, The Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
| | - Li-Xuan Sang
- Department of Gastroenterology, The Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
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13
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Abedalweli R, Nguyen M, Deodhar A. Combination biologics or targeted synthetic disease-modifying anti-rheumatic drugs in the treatment of spondyloarthritis: a systematic literature review. Expert Rev Clin Immunol 2024; 20:735-743. [PMID: 38512065 DOI: 10.1080/1744666x.2024.2327589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Accepted: 02/23/2024] [Indexed: 03/22/2024]
Abstract
INTRODUCTION The advent of biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) have transformed the management of immune-mediated rheumatic diseases, including spondylarthritis (SpA). However, the data about combining b/ts DMARDs in the treatment of SpA are scarce. The study objectives were to assess the efficacy and safety of combination b/tsDMARD in SpA. METHODS We conducted systematic literature review (PubMed and Medline) with two independent reviewers, one adjudicator, exploring the efficacy and safety of combination b/tsDMARDs in the treatment of SpA. Inclusion criteria were studies published in last 20 years, English language, interventions included use of two b/tsDMARDs, and minimal three-month follow-up. RESULTS Out of 1936 initial hits, 28 manuscripts fulfilled the inclusion criteria. Two were randomized controlled trials, and the remaining were retrospective cohort studies or case series. Combination of apremilast with bDMARD, or TNF inhibitor plus IL12/23 inhibitor were the commonest and reported good efficacy with no increased safety signal. CONCLUSIONS There is not enough data to fully evaluate efficacy and safety of combination b/tsDMARDs in SpA treatment. Limited information shows apremilast plus bDMARD, or TNF inhibitor plus IL12/23 inhibitor combination to be efficacious and safe. Randomized controlled trials and larger cohort with a longer follow-up are required.
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Affiliation(s)
- Rand Abedalweli
- Department of Medicine, Oregon Health & Science University/Hillsboro Medical Center, Portland, OR, USA
| | - Michelle Nguyen
- Department of Medicine, Providence St. Vincent Hospital, Portland, OR, USA
| | - Atul Deodhar
- Division of Arthritis and Rheumatic Diseases, Oregon Health & Science University, Portland, OR, USA
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14
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Kellar A, Dolinger MT, Spencer EA, Dubinsky MC. Real-World Outcomes of Dual Advanced Therapy in Children and Young Adults with Inflammatory Bowel Disease. Dig Dis Sci 2024; 69:1826-1833. [PMID: 38521850 DOI: 10.1007/s10620-024-08379-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 03/04/2024] [Indexed: 03/25/2024]
Abstract
BACKGROUND Data are limited on the safety and efficacy of combining advanced therapies for refractory patients with IBD. AIM To evaluate the real-world efficacy and safety of dual advanced therapy (DAT), combining 2 biologics or a biologic with a small molecule, in children and young adults with refractory IBD. METHODS Primary outcome of this single IBD center cohort was DAT remission (clinical and biomarker remission) at first assessment (T1). Secondary outcomes included remission at T2, if DAT de-intensification (De-I) occurred and T3, if T2 DAT re-intensification (Re-I) occurred. Efficacy and safety outcomes were described. RESULTS Of the 30 patients [43% female, 30% CD, median age of 18.3 [15.1-19.8] years], all 11 UST + TOFA achieved T1 remission; 6/10 De-I failed at T2; and 4/4 Re-I achieved T3 remission. Of 9 VDZ + TOFA, 6 achieved T1 remission; 5/6 De-I failed at T2; and 1/1 failed T3 Re-I. Of 4 UST + VDZ, 3 achieved T1 remission; 2/3 De-I failed at T2; and 0 had Re-I. Of 5 UST + UPA, 4 achieved T1 remission; 1/5 De-I failed at T2 but recaptured T3 remission post-Re-I. One VDZ + OZA achieved T1 remission and maintained T2 remission post-De-I to OZA monotherapy. At last follow-up, 43% were on original DAT, 17% on one of original DAT, and 40% neither. One UST + TOFA patient developed mild leukopenia and another developed septic arthritis and venous thromboembolism on VDZ + TOFA and prednisone. CONCLUSION Most children and young adults treated with DAT achieved remission with minimal safety events; however, de-intensification had limited success.
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Affiliation(s)
- Amelia Kellar
- Division of Pediatric Gastroenterology, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, USA.
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Comer Children's Hospital at the University of Chicago, 5839 S Maryland Avenue, MC 4065, Chicago, IL, 60637, USA.
| | - Michael T Dolinger
- Division of Pediatric Gastroenterology, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Elizabeth A Spencer
- Division of Pediatric Gastroenterology, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Marla C Dubinsky
- Division of Pediatric Gastroenterology, Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, USA
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15
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Bamidele AO, Mishra SK, Piovezani Ramos G, Hirsova P, Klatt EE, Abdelrahman LM, Sagstetter MR, Davidson HM, Fehrenbach PJ, Valenzuela-Pérez L, Kim Lee HS, Zhang S, Aguirre Lopez A, Kurdi AT, Westphal MS, Gonzalez MM, Gaballa JM, Kosinsky RL, Lee HE, Smyrk TC, Bantug G, Gades NM, Faubion WA. Interleukin 21 Drives a Hypermetabolic State and CD4 + T-Cell-Associated Pathogenicity in Chronic Intestinal Inflammation. Gastroenterology 2024; 166:826-841.e19. [PMID: 38266738 PMCID: PMC11034723 DOI: 10.1053/j.gastro.2024.01.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Revised: 11/23/2023] [Accepted: 01/15/2024] [Indexed: 01/26/2024]
Abstract
BACKGROUND & AIMS Incapacitated regulatory T cells (Tregs) contribute to immune-mediated diseases. Inflammatory Tregs are evident during human inflammatory bowel disease; however, mechanisms driving the development of these cells and their function are not well understood. Therefore, we investigated the role of cellular metabolism in Tregs relevant to gut homeostasis. METHODS Using human Tregs, we performed mitochondrial ultrastructural studies via electron microscopy and confocal imaging, biochemical and protein analyses using proximity ligation assay, immunoblotting, mass cytometry and fluorescence-activated cell sorting, metabolomics, gene expression analysis, and real-time metabolic profiling utilizing the Seahorse XF analyzer. We used a Crohn's disease single-cell RNA sequencing dataset to infer the therapeutic relevance of targeting metabolic pathways in inflammatory Tregs. We examined the superior functionality of genetically modified Tregs in CD4+ T-cell-induced murine colitis models. RESULTS Mitochondria-endoplasmic reticulum appositions, known to mediate pyruvate entry into mitochondria via voltage-dependent anion channel 1 (VDAC1), are abundant in Tregs. VDAC1 inhibition perturbed pyruvate metabolism, eliciting sensitization to other inflammatory signals reversible by membrane-permeable methyl pyruvate supplementation. Notably, interleukin (IL) 21 diminished mitochondria-endoplasmic reticulum appositions, resulting in enhanced enzymatic function of glycogen synthase kinase 3 β, a putative negative regulator of VDAC1, and a hypermetabolic state that amplified Treg inflammatory response. Methyl pyruvate and glycogen synthase kinase 3 β pharmacologic inhibitor (LY2090314) reversed IL21-induced metabolic rewiring and inflammatory state. Moreover, IL21-induced metabolic genes in Tregs in vitro were enriched in human Crohn's disease intestinal Tregs. Adoptively transferred Il21r-/- Tregs efficiently rescued murine colitis in contrast to wild-type Tregs. CONCLUSIONS IL21 triggers metabolic dysfunction associated with Treg inflammatory response. Inhibiting IL21-induced metabolism in Tregs may mitigate CD4+ T-cell-driven chronic intestinal inflammation.
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Affiliation(s)
- Adebowale O Bamidele
- Immunometabolism and Mucosal Immunity Laboratory, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Department of Immunology, Mayo Clinic, Rochester, Minnesota.
| | - Shravan K Mishra
- Immunometabolism and Mucosal Immunity Laboratory, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | | | - Petra Hirsova
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Emily E Klatt
- Department of Immunology, Mayo Clinic, Rochester, Minnesota
| | - Leena M Abdelrahman
- Immunometabolism and Mucosal Immunity Laboratory, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Mary R Sagstetter
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Heidi M Davidson
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Patrick J Fehrenbach
- Immunometabolism and Mucosal Immunity Laboratory, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | | | - Hyun Se Kim Lee
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Song Zhang
- Mayo Clinic Metabolomics Core, Mayo Clinic, Rochester, Minnesota; Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
| | - Abner Aguirre Lopez
- Immunometabolism and Mucosal Immunity Laboratory, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Ahmed T Kurdi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Maria S Westphal
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Michelle M Gonzalez
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Joseph M Gaballa
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | | | - Hee Eun Lee
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Thomas C Smyrk
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Glenn Bantug
- Immunobiology Laboratory, Department of Biomedicine, University Hospital of Basel, Basel, Switzerland
| | - Naomi M Gades
- Department of Comparative Medicine, Mayo Clinic, Scottsdale, Arizona
| | - William A Faubion
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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16
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Wils P, Jairath V, Sands BE, Reinisch W, Danese S, Peyrin-Biroulet L. Washout Periods in Inflammatory Bowel Disease Trials: A Systematic Literature Review and Proposed Solutions. Clin Gastroenterol Hepatol 2024; 22:896-898.e13. [PMID: 37743039 DOI: 10.1016/j.cgh.2023.09.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 09/08/2023] [Accepted: 09/08/2023] [Indexed: 09/26/2023]
Abstract
Inflammatory bowel diseases (IBD), encompassing ulcerative colitis (UC) and Crohn's disease (CD), impose a substantial burden. Despite many effective molecules, significant numbers of patients do not achieve clinical remission at 1 year1 and undergo surgery during their lives, revealing an important unmet need and therapeutic gap. Multiple randomized controlled trials (RCTs) are ongoing or planned to develop more effective and tolerable therapies. In parallel, a dramatic decline in recruitment rates has been observed. A multitude of factors have contributed to poor recruitment rates, including a long washout period between the investigational drug and prior advanced therapies (ie, biologic or small molecule drug).2,3 This study aims to review the different washout periods with prior advanced therapies or immunosuppressants in phase 3 RCTs for UC and CD and to propose potential solutions to ultimately improve the design of clinical studies and patient enrollment in future trials.
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Affiliation(s)
- Pauline Wils
- Department of Gastroenterology, Claude Huriez Hospital, University of Lille 2, Lille, France; Inserm, CHU Lille, U1286-INFINITE-Institute for Translational Research in Inflammation, University of Lille, Lille, France
| | - Vipul Jairath
- Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada
| | - Bruce E Sands
- The Dr Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Walter Reinisch
- Medical University of Vienna, Department of Internal Medicine III, Division Gastroenterology and Hepatology, Vienna, Austria
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and, Vita-Salute San Raffaele University, Milan, Italy
| | - Laurent Peyrin-Biroulet
- University of Lorraine, CHRU-Nancy, Department of Gastroenterology, Nancy, France; University of Lorraine, Inserm, NGERE, Nancy, France; Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Quebec, Canada.
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Li W, Lin J, Zhou J, He S, Wang A, Hu Y, Li H, Zou L, Liu Y. Hyaluronic acid-functionalized DDAB/PLGA nanoparticles for improved oral delivery of magnolol in the treatment of ulcerative colitis. Int J Pharm 2024; 653:123878. [PMID: 38325622 DOI: 10.1016/j.ijpharm.2024.123878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 01/21/2024] [Accepted: 02/02/2024] [Indexed: 02/09/2024]
Abstract
Dysfunction of the mucosal barrier as well as local inflammation are major challenges in the treatment of ulcerative colitis (UC). Mag, a natural compound derived from traditional Chinese medicine, has been shown to have anti-inflammatory and mucosal protection properties. However, its poor gastrointestinal stability as well as its insufficient accumulation in inflamed colonic lesions limit its potential use as an alternative therapeutic drug in UC. The present research involved the design and preparation of a hybrid nanoparticle system (LPNs) specifically targeting macrophages at the colonic site. This was achieved by electrostatically adsorbing HA onto positively charged lipid-polymer hybrid nanoparticles (HA-LPNs). The prepared HA-LPNs exhibited a rounded morphology and a narrow size distribution. In vitro, the anti-inflammatory efficacy of Mag-HA-LPNs (which control levels of the pro-inflammatory cytokines NO, IL-6 and TNF-α) was assessed in RAW 264.7 cells. Analysis by flow cytometry and fluorescence microscopy demonstrated increased cellular uptake through HA/CD44 interaction. As expected, Mag-HA-LPNs was found to effectively increased colon length and reduced DAI scores in DSS-treated mice. This effect was achieved by regulating the inflammatory cytokines level and promoting the restoration of the colonic mucosal barrier through increased expression of Claudin-1, ZO-1 and Occludin. In this study, we developed an efficient and user-friendly delivery method for the preparation of HA-functionalized PLGA nanoparticles, which are intended for oral delivery of Mag. The findings suggest that these HA-LPNs possess the potential to serve as a promising approach for direct drug delivery to the colon for effective treatment of UC.
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Affiliation(s)
- Wei Li
- School of Basic Medicine, Chengdu University, Chengdu 610106, People's Republic of China
| | - Jie Lin
- Affiliated Hospital & Clinical Medical College of Chengdu University, Chengdu University, Chengdu 610081, People's Republic of China; State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, People's Republic of China
| | - Jie Zhou
- School of Pharmacy, Chengdu University, Chengdu, 610106, People's Republic of China
| | - Siqi He
- School of Pharmacy, Chengdu University, Chengdu, 610106, People's Republic of China
| | - Anqi Wang
- School of Basic Medicine, Chengdu University, Chengdu 610106, People's Republic of China
| | - Yingfan Hu
- School of Basic Medicine, Chengdu University, Chengdu 610106, People's Republic of China
| | - Hanmei Li
- School of Food and Biological Engineering, Chengdu University, Chengdu 610106, People's Republic of China
| | - Liang Zou
- School of Food and Biological Engineering, Chengdu University, Chengdu 610106, People's Republic of China.
| | - Ya Liu
- Affiliated Hospital & Clinical Medical College of Chengdu University, Chengdu University, Chengdu 610081, People's Republic of China.
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Velikova T, Sekulovski M, Peshevska-Sekulovska M. Immunogenicity and Loss of Effectiveness of Biologic Therapy for Inflammatory Bowel Disease Patients Due to Anti-Drug Antibody Development. Antibodies (Basel) 2024; 13:16. [PMID: 38534206 PMCID: PMC10967499 DOI: 10.3390/antib13010016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 02/12/2024] [Accepted: 02/21/2024] [Indexed: 03/28/2024] Open
Abstract
Many patients with inflammatory bowel disease (IBD) experience a loss of effectiveness to biologic therapy (i.e., anti-TNF therapy, etc.). Therefore, in addition to the adverse effects of the treatment, these patients also face failure to achieve and maintain remission. Immunogenicity, the process of production of antibodies to biological agents, is fundamental to the evolution of loss of response to treatment in IBD patients. The presence of these antibodies in patients is linked to decreased serum drug levels and inhibited biological activity. However, immunogenicity rates exhibit significant variability across inflammatory disease states, immunoassay formats, and time periods. In this review, we aimed to elucidate the immunogenicity and immune mechanisms of antibody formation to biologics, the loss of therapy response, clinical results of biological treatment for IBD from systematic reviews and meta-analyses, as well as to summarize the most recent strategies for overcoming immunogenicity and approaches for managing treatment failure in IBD.
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Affiliation(s)
- Tsvetelina Velikova
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria; (T.V.); (M.S.)
| | - Metodija Sekulovski
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria; (T.V.); (M.S.)
- Department of Anesthesiology and Intensive Care, University Hospital Lozenetz, 1 Kozyak Str., 1407 Sofia, Bulgaria
| | - Monika Peshevska-Sekulovska
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria; (T.V.); (M.S.)
- Department of Gastroenterology, University Hospital Lozenetz, 1407 Sofia, Bulgaria
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Vebr M, Pomahačová R, Sýkora J, Schwarz J. A Narrative Review of Cytokine Networks: Pathophysiological and Therapeutic Implications for Inflammatory Bowel Disease Pathogenesis. Biomedicines 2023; 11:3229. [PMID: 38137450 PMCID: PMC10740682 DOI: 10.3390/biomedicines11123229] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 10/11/2023] [Accepted: 11/22/2023] [Indexed: 12/24/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a lifelong inflammatory immune mediated disorder, encompassing Crohn's disease (CD) and ulcerative colitis (UC); however, the cause and specific pathogenesis of IBD is yet incompletely understood. Multiple cytokines produced by different immune cell types results in complex functional networks that constitute a highly regulated messaging network of signaling pathways. Applying biological mechanisms underlying IBD at the single omic level, technologies and genetic engineering enable the quantification of the pattern of released cytokines and new insights into the cytokine landscape of IBD. We focus on the existing literature dealing with the biology of pro- or anti-inflammatory cytokines and interactions that facilitate cell-based modulation of the immune system for IBD inflammation. We summarize the main roles of substantial cytokines in IBD related to homeostatic tissue functions and the remodeling of cytokine networks in IBD, which may be specifically valuable for successful cytokine-targeted therapies via marketed products. Cytokines and their receptors are validated targets for multiple therapeutic areas, we review the current strategies for therapeutic intervention and developing cytokine-targeted therapies. New biologics have shown efficacy in the last few decades for the management of IBD; unfortunately, many patients are nonresponsive or develop therapy resistance over time, creating a need for novel therapeutics. Thus, the treatment options for IBD beyond the immune-modifying anti-TNF agents or combination therapies are expanding rapidly. Further studies are needed to fully understand the immune response, networks of cytokines, and the direct pathogenetic relevance regarding individually tailored, safe and efficient targeted-biotherapeutics.
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Affiliation(s)
- Marek Vebr
- Departments of Pediatrics, Faculty Hospital, Faculty of Medicine in Pilsen, Charles University of Prague, 323 00 Pilsen, Czech Republic; (R.P.); (J.S.); (J.S.)
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20
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Abstract
OBJECTIVE To describe and review the published evidence on use of multiple biologics within specialty pharmacy practice. DATA SOURCES A search of PubMed and Embase was conducted from October 2021 through September 2022. Keywords included biologics for immune-mediated conditions along with the terms "dual," "add-on," and "combination." STUDY SELECTION AND DATA EXTRACTION All human studies in the English language were considered. Published abstracts, case reports, case series, randomized controlled trials, systematic reviews, and meta-analyses were included. DATA SYNTHESIS Although evidence is limited, there are published meta-analyses of combined biologic use within gastroenterology and rheumatology. There are also numerous case reports within dermatology. Clinical trials of dual biologics for severe rheumatologic conditions and inflammatory bowel disease are in progress. Existing evidence for use in pulmonology and allergy suggest dual biologic therapy can be safe and effective, but data are limited. Literature describing use of monoclonal antibodies for other overlapping conditions is lacking. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE This article reviews the evidence describing combination biologic use and outlines remaining knowledge gaps. It also describes the essential role that specialty pharmacists play in managing therapeutic mAbs. CONCLUSIONS High-quality evidence describing combination biologic use is limited and long-term safety data are lacking. Pharmacists should utilize their specialized training to assess appropriateness of therapy, provide patient counseling and monitor for safety and efficacy.
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Affiliation(s)
- Lauren C Quiroga
- Department of Pharmacy Services, University of Michigan Health, Ann Arbor, MI, USA
| | - Ashley A Sabourin
- Department of Pharmacy Services, University of Michigan Health, Ann Arbor, MI, USA
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21
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Li D, Li J, Chen T, Qin X, Pan L, Lin X, Liang W, Wang Q. Injectable Bioadhesive Hydrogels Scavenging ROS and Restoring Mucosal Barrier for Enhanced Ulcerative Colitis Therapy. ACS APPLIED MATERIALS & INTERFACES 2023; 15:38273-38284. [PMID: 37530040 DOI: 10.1021/acsami.3c06693] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/03/2023]
Abstract
Despite the progress in the therapy of ulcerative colitis (UC), long-lasting UC remission can hardly be achieved in the majority of UC patients. The key pathological characteristics of UC include an impaired mucosal barrier and local inflammatory infiltration. Thus, a two-pronged approach aiming at repairing damaged mucosal barrier and scavenging inflammatory mediators simultaneously might hold great potential for long-term remission of UC. A rectal formulation can directly offer preferential and effective drug delivery to inflamed colon. However, regular intestinal peristalsis and frequent diarrhea in UC might cause transient drug retention. Therefore, a bioadhesive hydrogel with strong interaction with intestinal mucosa might be preferable for rectal administration to prolong drug retention. Here, we designed a bioadhesive hydrogel formed by the cross-linking of sulfhydryl chondroitin sulfate and polydopamine (CS-PDA). The presence of PDA would ensure the mucosa-adhesive behavior, and the addition of CS in the hydrogel network was expected to achieve the restoration of the intestinal epithelial barrier. To scavenge the key player (excessive reactive oxygen species, ROS) in inflamed colon, sodium ferulic (SF), a potent ROS inhibitor, was incorporated into the CS-PDA hydrogel. After rectal administration, the SF-loaded CS-PDA hydrogel could adhere to the colonic mucosa to allow prolonged drug retention. Subsequently, sustained SF release could be achieved to persistently scavenge ROS in inflammatory areas. Meanwhile, the presence of CS would promote the restoration of the mucosal barrier. Ultimately, scavenging ROS and restoring the mucosal barrier could be simultaneously achieved via this SF-loaded bioadhesive hydrogel scaffold. Our two-pronged approach might provide new insight for effective UC treatment.
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Affiliation(s)
- Daming Li
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education and School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Jiao Li
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education and School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Tao Chen
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education and School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Xianyan Qin
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education and School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Lihua Pan
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education and School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Xin Lin
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education and School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Wenlang Liang
- Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu 610031, China
| | - Qin Wang
- Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu 610031, China
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22
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Yang J, Peng M, Tan S, Ge S, Xie L, Zhou T, Liu W, Zhang K, Zhang Z, Liu J, Shi J. Calcium Tungstate Microgel Enhances the Delivery and Colonization of Probiotics during Colitis via Intestinal Ecological Niche Occupancy. ACS CENTRAL SCIENCE 2023; 9:1327-1341. [PMID: 37521784 PMCID: PMC10375893 DOI: 10.1021/acscentsci.3c00227] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Indexed: 08/01/2023]
Abstract
The effective delivery and colonization of probiotics are recommended for therapeutic interventions during colitis, the efficacy of which is hampered by abnormally colonized Enterobacteriaceae at pathological sites. To improve the delivery and colonization of probiotics, a calcium tungstate microgel (CTM)-based oral probiotic delivery system is proposed herein. CTM can selectively disrupt the ecological niche occupied by abnormally expanded Enterobacteriaceae during colitis to facilitate probiotic colonization. In addition, the calcium-binding protein, calprotectin, which is highly expressed in colitis, efficiently extracts calcium from CTM and releases tungsten to inhibit Enterobacteriaceae by displacing molybdenum in the molybdenum enzyme, without affecting the delivered probiotics. Moreover, CTM demonstrated resistance to the harsh environment of the gastrointestinal (GI) tract and to intestinal adhesion. The synergistic reduction of Enterobacteriaceae by 45 times and the increase in probiotic colonization by 25 times, therefore, result in a remarkable treatment for colitis, including restoration of colonic length, effective downregulation of the inflammatory response, restoration of the damaged mucosal barrier, and restoration of gut microbiome homeostasis.
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Affiliation(s)
- Jiali Yang
- School
of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, P. R. China
- Key
Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou 450001, P. R. China
| | - Mengyun Peng
- School
of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, P. R. China
- Key
Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou 450001, P. R. China
| | - Shaochong Tan
- School
of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, P. R. China
- Key
Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou 450001, P. R. China
| | - Shengchan Ge
- School
of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, P. R. China
- Key
Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou 450001, P. R. China
| | - Li Xie
- School
of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, P. R. China
- Key
Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou 450001, P. R. China
| | - Tonghai Zhou
- School
of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, P. R. China
- Key
Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou 450001, P. R. China
| | - Wei Liu
- School
of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, P. R. China
- Key
Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou 450001, P. R. China
| | - Kaixiang Zhang
- School
of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, P. R. China
- Key
Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou 450001, P. R. China
- Collaborative
Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou 450001, P. R. China
| | - Zhenzhong Zhang
- School
of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, P. R. China
- Key
Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou 450001, P. R. China
- Collaborative
Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou 450001, P. R. China
| | - Junjie Liu
- School
of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, P. R. China
- Key
Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou 450001, P. R. China
- Collaborative
Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou 450001, P. R. China
| | - Jinjin Shi
- School
of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, P. R. China
- Key
Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou 450001, P. R. China
- Collaborative
Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou 450001, P. R. China
- State
Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou, 450001, P. R. China
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23
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Bamidele AO, Mishra SK, Hirsova P, Fehrenbach PJ, Valenzuela-Pérez L, Lee HSK. Interleukin-21 Drives a Hypermetabolic State and CD4 + T Cell-associated Pathogenicity in Chronic Intestinal Inflammation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.02.543518. [PMID: 37333332 PMCID: PMC10274654 DOI: 10.1101/2023.06.02.543518] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/20/2023]
Abstract
BACKGROUND & AIMS Incapacitated regulatory T cells (Tregs) contribute to immune-mediated diseases. Inflammatory Tregs are evident during human inflammatory bowel disease (IBD); however, mechanisms driving the development of these cells and their function are not well understood. Therefore, we investigated the role of cellular metabolism in Tregs relevant to gut homeostasis. METHODS Using human Tregs, we performed mitochondrial ultrastructural studies via electron microscopy and confocal imaging, biochemical and protein analyses using proximity ligation assay, immunoblotting, mass cytometry and fluorescence-activated cell sorting, metabolomics, gene expression analysis, and real-time metabolic profiling utilizing Seahorse XF analyzer. We utilized Crohn's disease single-cell RNA sequencing dataset to infer therapeutic relevance of targeting metabolic pathways in inflammatory Tregs. We examined the superior functionality of genetically-modified Tregs in CD4+ T cell-induced murine colitis models. RESULTS Mitochondria-endoplasmic reticulum (ER) appositions, known to mediate pyruvate entry into mitochondria via VDAC1, are abundant in Tregs. VDAC1 inhibition perturbed pyruvate metabolism, eliciting sensitization to other inflammatory signals reversible by membrane-permeable methyl pyruvate (MePyr) supplementation. Notably, IL-21 diminished mitochondria-ER appositions, resulting in enhanced enzymatic function of glycogen synthase kinase 3 β (GSK3β), a putative negative regulator of VDAC1, and a hypermetabolic state that amplified Treg inflammatory response. MePyr and GSK3β pharmacologic inhibitor (LY2090314) reversed IL-21-induced metabolic rewiring and inflammatory state. Moreover, IL-21-induced metabolic genes in Tregs in vitro were enriched in human Crohn's disease intestinal Tregs. Adoptively transferred Il21r-/- Tregs efficiently rescued murine colitis in contrast to wild-type Tregs. CONCLUSIONS IL-21 triggers metabolic dysfunction associated with Treg inflammatory response. Inhibiting IL-21-induced metabolism in Tregs may mitigate CD4+ T cell-driven chronic intestinal inflammation.
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Affiliation(s)
- Adebowale O Bamidele
- Immunometabolism and Mucosal Immunity Laboratory, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
- Department of Immunology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
| | - Shravan K Mishra
- Immunometabolism and Mucosal Immunity Laboratory, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
| | - Petra Hirsova
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
| | - Patrick J Fehrenbach
- Immunometabolism and Mucosal Immunity Laboratory, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
| | - Lucia Valenzuela-Pérez
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
| | - Hyun Se Kim Lee
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
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24
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Berinstein EM, Sheehan JL, Jacob J, Steiner CA, Stidham RW, Shannon C, Bishu S, Levine J, Cohen-Mekelburg SA, Waljee AK, Higgins PDR, Berinstein JA. Efficacy and Safety of Dual Targeted Therapy for Partially or Non-responsive Inflammatory Bowel Disease: A Systematic Review of the Literature. Dig Dis Sci 2023; 68:2604-2623. [PMID: 36807832 PMCID: PMC9942632 DOI: 10.1007/s10620-023-07837-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 01/13/2023] [Indexed: 02/23/2023]
Abstract
BACKGROUND Dual targeted therapy (DTT) has emerged as an attractive therapeutic option for select patients with active inflammatory bowel disease (IBD) who are unable to achieve remission with biologic or small molecule monotherapy. We conducted a systematic review of specific DTT combinations in patients with IBD. METHODS We conducted a systematic search of MEDLINE, EMBASE, Scopus, CINAHL Complete, Web of Science Core Collection, and Cochrane Library to identify articles related to the use of DTT for the treatment of Crohn Disease (CD) or ulcerative colitis (UC) published before February 2021. RESULTS Twenty-nine studies were identified comprising 288 patients started on DTT for partially or non-responsive IBD. We identified 14 studies with 113 patients receiving anti-tumor necrosis factor (TNF) and anti-integrin therapies (i.e., vedolizumab and natalizumab), 12 studies with 55 patients receiving vedolizumab and ustekinumab, nine studies with 68 patients receiving vedolizumab and tofacitinib, five studies with 24 patients receiving anti-TNF therapy and tofacitinib, six studies with 18 patients receiving anti-TNF therapy and ustekinumab, and three studies with 13 patients receiving ustekinumab and tofacitinib. CONCLUSION DTT is a promising approach to improve IBD treatment for patients with incomplete responses to targeted monotherapy. Larger prospective clinical studies are needed to confirm these findings as is additional predictive modeling to identify the patient subgroups most likely to require and benefit from this approach.
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Affiliation(s)
- Elliot M Berinstein
- Department of Medicine, Trinity Health Ann Arbor Hospital, Ypsilanti, MI, USA
| | - Jessica L Sheehan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109, USA
- Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor, MI, USA
| | - Janson Jacob
- Department of Internal Medicine, Michigan Medicine, Ann Arbor, MI, USA
| | - Calen A Steiner
- Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Ryan W Stidham
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109, USA
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | - Carol Shannon
- Taubman Health Sciences Library, University of Michigan, Ann Arbor, MI, USA
| | - Shrinivas Bishu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109, USA
| | - Jake Levine
- Department of Internal Medicine, Michigan Medicine, Ann Arbor, MI, USA
| | - Shirley A Cohen-Mekelburg
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109, USA
- Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor, MI, USA
- VA Center for Clinical Management Research, VA Ann Arbor Health Care System, Ann Arbor, MI, USA
| | - Akbar K Waljee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109, USA
- Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor, MI, USA
- VA Center for Clinical Management Research, VA Ann Arbor Health Care System, Ann Arbor, MI, USA
- Department of Learning Health Sciences, University of Michigan, Ann Arbor, MI, USA
| | - Peter D R Higgins
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109, USA
| | - Jeffrey A Berinstein
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109, USA.
- Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor, MI, USA.
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25
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McCormack MD, Wahedna NA, Aldulaimi D, Hawker P. Emerging role of dual biologic therapy for the treatment of inflammatory bowel disease. World J Clin Cases 2023; 11:2621-2630. [PMID: 37214562 PMCID: PMC10198105 DOI: 10.12998/wjcc.v11.i12.2621] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 02/07/2023] [Accepted: 03/24/2023] [Indexed: 04/25/2023] Open
Abstract
Biologic agents have now been used in the management of inflammatory bowel disease (IBD) for many years where experience, expertise and confidence in their use has developed over time. In the United Kingdom, there are well established guidelines and recommendations for both single agent biologic treatments, and with combination therapy of a biologic agent with a small molecule agent in maintenance therapy. In recent times, there has been increasing interest and experience using dual biologic therapy (DBT) in IBD, primarily in difficult to treat and refractory cases with high disease burden. However, published data on use, experience and safety profiles is limited and large-scale studies remain low in number in this developing area. We therefore aim to present a summary and review of the available published data in this area to help us better understand the emerging role of DBT in IBD.
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Affiliation(s)
- Matthew D McCormack
- Department of Gastroenterology, South Warwickshire NHS Foundation Trust, Warwick Hospital, Warwick CV34 5BW, United Kingdom
| | - Natasha A Wahedna
- Department of Gastroenterology, South Warwickshire NHS Foundation Trust, Warwick Hospital, Warwick CV34 5BW, United Kingdom
| | - David Aldulaimi
- Department of Gastroenterology, South Warwickshire NHS Foundation Trust, Warwick Hospital, Warwick CV34 5BW, United Kingdom
| | - Peter Hawker
- Department of Gastroenterology, South Warwickshire NHS Foundation Trust, Warwick Hospital, Warwick CV34 5BW, United Kingdom
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26
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Li X, Qiao G, Chu L, Lin L, Zheng G. Smilax china L. Polysaccharide Alleviates Dextran Sulphate Sodium-Induced Colitis and Modulates the Gut Microbiota in Mice. Foods 2023; 12:foods12081632. [PMID: 37107427 PMCID: PMC10137970 DOI: 10.3390/foods12081632] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 03/27/2023] [Accepted: 03/31/2023] [Indexed: 04/29/2023] Open
Abstract
This work aimed to investigate the preventive effect of Smilax china L. polysaccharide (SCP) on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice. Smilax china L. polysaccharide was isolated by hot water extraction, ethanol precipitation, deproteinization, and purification using DEAE-cellulose column chromatography to yield three polysaccharides: SCP_C, SCP_A, and SCP_N. Acute colitis was induced by administering 3% (w/v) DSS in drinking water for 7 days. Sulfasalazine, SCP_C, SCP_A, and SCP_N were administered by gavage for 9 days. SCP_C, SCP_A, and SCP_N could significantly improve symptoms, as evidenced by the declining disease activity index (DAI), decreased spleen weight, increased length of the colon, and improved colonic histology. Moreover, SCP_C, SCP_A, and SCP_N increased serum glutathione and decreased the levels of pro-inflammatory cytokines, malondialdehyde, nitric oxide, and myeloperoxidase in colon tissues. Additionally, SCP_C, SCP_A, and SCP_N modulated gut microbiota via ascending the growth of Lachnospiraceae, Muribaculaceae, Blautia, and Mucispirillum and descending the abundance of Akkermansiaceae, Deferribacteraceae, and Oscillibacter in mice with UC. The results suggested that Smilax china L. polysaccharide ameliorates oxidative stress, balances inflammatory cytokines, and modulates gut microbiota, providing an effective therapeutic strategy for UC in mice.
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Affiliation(s)
- Xin Li
- Jiangxi Key Laboratory of Natural Product and Functional Food, College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang 330045, China
| | - Gaoxiang Qiao
- Jiangxi Key Laboratory of Natural Product and Functional Food, College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang 330045, China
| | - Lulu Chu
- Jiangxi Key Laboratory of Natural Product and Functional Food, College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang 330045, China
| | - Lezhen Lin
- Jiangxi Key Laboratory of Natural Product and Functional Food, College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang 330045, China
| | - Guodong Zheng
- Jiangxi Key Laboratory of Natural Product and Functional Food, College of Food Science and Engineering, Jiangxi Agricultural University, Nanchang 330045, China
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27
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Li M, Liu J, Shi L, Zhou C, Zou M, Fu D, Yuan Y, Yao C, Zhang L, Qin S, Liu M, Cheng Q, Wang Z, Wang L. Gold nanoparticles-embedded ceria with enhanced antioxidant activities for treating inflammatory bowel disease. Bioact Mater 2023; 25:95-106. [PMID: 36789001 PMCID: PMC9900456 DOI: 10.1016/j.bioactmat.2023.01.015] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 01/16/2023] [Accepted: 01/16/2023] [Indexed: 01/27/2023] Open
Abstract
The excessive reactive oxygen species (ROS) is a hallmark associated with the initiation and progression of inflammatory bowel disease (IBD), which execrably form a vicious cycle of ROS and inflammation to continually promote disease progression. Here, the gold nanoparticles-embedded ceria nanoparticles (Au/CeO2) with enhanced antioxidant activities are designed to block this cycle reaction for treating IBD by scavenging overproduced ROS. The Au/CeO2 with core-shell and porous structure exhibits significantly higher enzymatic catalytic activities compared with commercial ceria nanoparticles, likely due to the effective exposure of catalytic sites, higher content of Ce (III) and oxygen vacancy, and accelerated reduction from Ce (IV) to Ce (III). Being coated with negatively-charged hyaluronic acid, the Au/CeO2@HA facilitates accumulation in inflamed colon tissues via oral administration, reduces pro-inflammatory cytokines, and effectively alleviates colon injury in colitis mice. Overall, the Au/CeO2@HA with good biocompatibility is a promising nano-therapeutic for treating IBD.
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Affiliation(s)
- Mingyi Li
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China,Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China,Hubei Key Laboratory of Regenerative Medicine and Multi-disciplinary Translational Research, Wuhan, 430022, China
| | - Jia Liu
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China,Hubei Key Laboratory of Regenerative Medicine and Multi-disciplinary Translational Research, Wuhan, 430022, China
| | - Lin Shi
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China,Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China,Hubei Key Laboratory of Regenerative Medicine and Multi-disciplinary Translational Research, Wuhan, 430022, China
| | - Cheng Zhou
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China,Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430022, China,Hubei Key Laboratory of Regenerative Medicine and Multi-disciplinary Translational Research, Wuhan, 430022, China
| | - Meizhen Zou
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China,Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China,Hubei Key Laboratory of Regenerative Medicine and Multi-disciplinary Translational Research, Wuhan, 430022, China
| | - Daan Fu
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China,Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430022, China
| | - Ye Yuan
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China,Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430022, China
| | - Chundong Yao
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China,Hubei Key Laboratory of Regenerative Medicine and Multi-disciplinary Translational Research, Wuhan, 430022, China
| | - Lifang Zhang
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Sumei Qin
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China,Hubei Key Laboratory of Regenerative Medicine and Multi-disciplinary Translational Research, Wuhan, 430022, China
| | - Miaodeng Liu
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China,Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China,Hubei Key Laboratory of Regenerative Medicine and Multi-disciplinary Translational Research, Wuhan, 430022, China
| | - Qian Cheng
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China,Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China,Hubei Key Laboratory of Regenerative Medicine and Multi-disciplinary Translational Research, Wuhan, 430022, China
| | - Zheng Wang
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China,Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430022, China,Hubei Key Laboratory of Regenerative Medicine and Multi-disciplinary Translational Research, Wuhan, 430022, China,Corresponding author. Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Lin Wang
- Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China,Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China,Hubei Key Laboratory of Regenerative Medicine and Multi-disciplinary Translational Research, Wuhan, 430022, China,Corresponding author. Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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28
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Guillo L, Flachaire B, Avouac J, Dong C, Nachury M, Bouguen G, Buisson A, Caillo L, Fumery M, Gilletta C, Hébuterne X, Lafforgue P, Laharie D, Mahé E, Marotte H, Nancey S, Ottaviani S, Salmon JH, Savoye G, Serrero M, Uzzan M, Viguier M, Richez C, Peyrin-Biroulet L, Seksik P, Pham T. Efficacy and safety of combination targeted therapies in immune-mediated inflammatory disease: the COMBIO study. Dig Liver Dis 2023; 55:61-68. [PMID: 35985961 DOI: 10.1016/j.dld.2022.07.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 07/19/2022] [Accepted: 07/20/2022] [Indexed: 12/31/2022]
Abstract
BACKGROUND Use of a combination of targeted therapies (COMBIO) in patients with refractory/overlapping immune-mediated inflammatory diseases (IMIDs) has increased, but reported data remain scarce. We aimed to assess effectiveness and safety of COMBIO in patients with IMIDs. METHODS We conducted a French ambispective multicenter cohort study from September 2020 to May 2021, including adults' patients with 1 or 2 IMIDs and treated at least 3-month with COMBIO. RESULTS Overall, 143 patients were included. The most common IMIDs were Crohn's disease (63.6%), axial spondyloarthritis (37.7%), and ulcerative colitis (14%). Half of patients had only one IMID, of which 60% were Crohn's disease. Mean duration of COMBIO was 274.5±59.3 weeks, and COMBIO persistence at 104 weeks was estimated at 64.1%. The most frequent COMBIOs combined anti-TNF agents with vedolizumab (30%) or ustekinumab (28.7%). Overall, 50% of patients achieved significant and 27% mild-to-moderate improvement in patient-reported outcomes. Extended duration of COMBIO (aOR=1.09; 95% CI: 1.03-1.14; p=0.002) and diagnoses of two IMIDs (aOR=3.46; 95%CI: 1.29-9.26; p=0.013) were associated with significant improvement in patient-reported outcomes. Incidence of serious infection during COMBIO was 4.51 per 100 person-years (95% CI 2.20-8.27) and 5 COMBIOs were discontinued due to adverse events. CONCLUSIONS COMBIO can be effective and safe in patients with refractory/overlapping IMIDs.
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Affiliation(s)
- Lucas Guillo
- Aix Marseille Univ, APHM, University Hospital of Marseille Nord, Department of Gastroenterology, Marseille, France.
| | - Benoit Flachaire
- Aix Marseille Univ, APHM, University Hospital of Marseille Sainte-Marguerite, Department of Rheumatology, Marseille, France
| | - Jérôme Avouac
- Université de Paris, service de rhumatologie, hôpital Cochin, AP-HP.CUP, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France
| | - Catherine Dong
- Service de Gastro-Entérologie, Assistance publique-Hôpitaux de Paris (AP-HP), hôpital Bicêtre, 94270 Le Kremlin-Bicêtre, France
| | - Maria Nachury
- Université de Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, F-59000 Lille, France
| | - Guillaume Bouguen
- CHU Rennes, Univ Rennes, INSERM, CIC1414, Institut NUMECAN (Nutrition Metabolisms and Cancer), 35000 Rennes, France
| | - Anthony Buisson
- Université Clermont Auvergne, 3iHP, CHU Clermont-Ferrand, Service d'Hépato-Gastroentérologie, Inserm U1071, M2iSH, USC-INRA 2018, Clermont-Ferrand, France
| | - Ludovic Caillo
- Department of Gastroenterology, University Hospital of Nimes, Nimes, France
| | - Mathurin Fumery
- Department of Gastroenterology, Amiens University Medical Center and PeriTox UMR I-O1, Jules Verne University of Picardie, Amiens, France
| | - Cyrielle Gilletta
- Department of Gastroenterology, Toulouse University Hospital, Toulouse, France
| | - Xavier Hébuterne
- Gastroenterology and Clinical Nutrition, CHU of Nice, University Côte d'Azur, Nice, France
| | - Pierre Lafforgue
- Aix Marseille Univ, APHM, University Hospital of Marseille Sainte-Marguerite, Department of Rheumatology, Marseille, France
| | - David Laharie
- CHU de Bordeaux, Hôpital Haut-Lévêque, Service d'Hépato-gastroentérologie et oncologie digestive - Université de Bordeaux, F-33000 Bordeaux, France
| | - Emmanuel Mahé
- Dermatology Department, Hôpital Victor Dupouy, Argenteuil, France. Groupe de recherche sur le Psoriasis (GrPso) de la Société Française de Dermatologie
| | - Hubert Marotte
- Department of Rheumatology, Inserm U1059-LBTO, CHU Saint-Etienne, Saint-Etienne, France
| | - Stéphane Nancey
- Department of Gastroenterology, Inserm U1111-CIRI, Lyon-Sud University Hospital, Hospices Civils de Lyon, Pierre Bénite, France
| | - Sébastien Ottaviani
- Departement of Rheumatology, DMU Locomotion, Hôpital Bichat-Claude Bernard, APHP, Université de Paris, Paris, France
| | - Jean-Hugues Salmon
- Department of Rheumatology and EA 3797, University of Reims Champagne-Ardenne, Reims, France
| | - Guillaume Savoye
- Department of Gastroenterology, Rouen University Hospital, Rouen, France
| | - Mélanie Serrero
- Aix Marseille Univ, APHM, University Hospital of Marseille Nord, Department of Gastroenterology, Marseille, France
| | - Mathieu Uzzan
- Department of Gastroenterology, IBD unit, Beaujon Hospital, APHP, Clichy, France
| | - Manuelle Viguier
- Department of Dermatology-Venereology, Hôpital Robert Debré, Université Reims Champagne-Ardenne, Reims, France
| | - Christophe Richez
- Rheumatology Department, CHU de Bordeaux, and ImmunoConcEpt, CNRS, UMR 5164, University of Bordeaux, Bordeaux, France
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology and INSERM NGERE U1256, University Hospital of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France
| | - Philipe Seksik
- Department of Gastroenterology, Centre de recherche Saint-Antoine, Sorbonne Université, INSERM, APHP, Hôpital Saint-Antoine, Paris, France
| | - Thao Pham
- Aix Marseille Univ, APHM, University Hospital of Marseille Sainte-Marguerite, Department of Rheumatology, Marseille, France
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Xu YH, Zhu WM, Guo Z. Current status of novel biologics and small molecule drugs in the individualized treatment of inflammatory bowel disease. World J Gastroenterol 2022; 28:6888-6899. [PMID: 36632311 PMCID: PMC9827580 DOI: 10.3748/wjg.v28.i48.6888] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 11/11/2022] [Accepted: 12/01/2022] [Indexed: 12/26/2022] Open
Abstract
Treatment strategies for inflammatory bowel disease (IBD) are rapidly evolving with the development of biologics and small molecule drugs (SMDs). However, these drugs are not guaranteed to be effective in all patients, and a "ceiling effect" of biologic monotherapy may occur. This issue highlights an unmet need for optimizing the use of biologics and predicting therapeutic responses. Thus, the development of new drugs with novel mechanisms of action is urgently needed for patients with primary nonresponse and secondary loss of response to conventional biologics and SMDs. In addition, combining different biologics or SMDs has been proposed as a novel strategy to enhance treatment efficacy in IBD, which theoretically has multidimensional anti-inflammatory potential. Based on the current evidence available for IBD, dual targeted therapy may be a promising strategy for refractory IBD patients who have failed in multiple biologic trea-tments or who have extraintestinal manifestation. Additionally, identifying the subgroup of IBD patients who are responding to biological combination therapies is also equally important in stable disease remission. In this review, we sum-marize the newly developed biologics and SMDs and the current status of bio-logics/SMDs to highlight the development of individualized treatment in IBD.
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Affiliation(s)
- Yi-Han Xu
- Department of General Surgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Wei-Ming Zhu
- Department of General Surgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Zhen Guo
- Department of General Surgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
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30
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Dual Biologic Therapy in Moderate to Severe Pediatric Inflammatory Bowel Disease: A Retrospective Study. CHILDREN (BASEL, SWITZERLAND) 2022; 10:children10010011. [PMID: 36670562 PMCID: PMC9856313 DOI: 10.3390/children10010011] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 12/13/2022] [Accepted: 12/17/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Inflammatory bowel diseases in children are characterized by a wide variety of symptoms and often a severe clinical course. In the treatment, we aimed to induce and maintain remission. We focused on assessing the efficacy and safety of the concomitant use of two biologic therapies including: anti-TNF (infliximab, adalimumab) vedolizumab and ustekinumab in a refractory pediatric IBD cohort. METHODS Fourteen children (nine ulcerative colitis, one ulcerative colitis/IBD-unspecified, four Crohn's disease) with a disease duration of 5.2 (8 months-14 years) years, initiated dual therapy at an age of 11.7 (3-17) years after failure of monotherapy with a biological drug. Five patients (36%) were treated with vedolizumab/adalimumab (VDZ + ADA), five (36%) with ustekinumab/adalimumab (UST + ADA), and three (21%) with infliximab/vedolizumab (IFX + VDZ). One patient (7%) was switched from a combination of vedolizumab and adalimumab to ustekinumab and adalimumab during follow-up. RESULTS A clinical improvement was obtained in ten children (73%; 5 UC, 1 UC/IBD-unspecified, 4 CD) on the PCDAI/PUCAI scale after 4 months of a second biological drug being added. The median fecal calprotectin decreased from 1610 µg/g (140-10,100) to 586 µg/g (5-3410; p = 0.028) between baseline and 4 months. CONCLUSIONS Our clinical experience suggests that dual therapy may be an option for pediatric patients with moderate and severe courses of IBD with limited therapeutic options.
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31
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Blue light irradiation alleviated dextran sulfate sodium-induced colitis mediated by the Bmal1 pathway in macrophages. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY 2022. [DOI: 10.1016/j.jpap.2022.100156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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32
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Abdullah I, AlMojil K, Shehab M. Effectiveness of Dual Biologic or Small Molecule Therapy for Achieving Endoscopic Remission in Refractory Inflammatory Bowel Disease. Diseases 2022; 10:102. [PMID: 36412596 PMCID: PMC9680431 DOI: 10.3390/diseases10040102] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 10/06/2022] [Accepted: 11/02/2022] [Indexed: 11/12/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic autoimmune disease with relapse-remission courses. A number of patients may present with a refractory disease with partial or no response to treatment. Others may present with extra-intestinal manifestations that makes the treatment with one biologic challenging. Dual target therapy (DTT), combining biologics and/or small molecule drugs, may offer a chance to achieve remission in these cases and improve patients' quality of life despite the limited evidence regarding this approach. We present a case series of refractory inflammatory bowel disease cases managed with DTT. Seven patients with refractory IBD achieved steroid free, clinical, and endoscopic remission by using DTT. These results support that DTT could be an effective approach in selected patients with refractory IBD or with concomitant extra-intestinal manifestations (EIM). Larger studies, ideally randomized controlled trials, are needed to further support the evidence and confirm the efficacy and safety of DTT for IBD.
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Affiliation(s)
- Israa Abdullah
- Department of Pharmacy, Clinical Pharmacy Unit, Kuwait Hospital, Sabah Al-Salem 44001, Kuwait
| | - Khaled AlMojil
- Division of Gastroenterology, Department of Internal Medicine, Mubarak Alkabeer University Hospital, Kuwait University, Jabriya 47060, Kuwait
| | - Mohammad Shehab
- Division of Gastroenterology, Department of Internal Medicine, Mubarak Alkabeer University Hospital, Kuwait University, Jabriya 47060, Kuwait
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33
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Vuyyuru SK, Kedia S, Ahuja V. Considerations when starting patients on multiple biologics and small molecules. Curr Opin Gastroenterol 2022; 38:562-569. [PMID: 36165042 DOI: 10.1097/mog.0000000000000886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
PURPOSE OF REVIEW Inflammatory bowel disease (IBD) is complex disease that poses significant economic, and psychological burden on patients. Despite advent of newer biologics and small molecules targeting different aspects of immunopathogenesis, there appears to be a plateau in clinical outcomes. In this review we discuss the role of multiple biologics, existing evidence and various considerations when prescribing multiple biologics. RECENT FINDINGS Recent scientific advances helped to unravel the pathophysiology of inflammatory bowel disease and newer cytokines have been identified which can be potential targets in the management of IBD. Targeting more than one cytokine appears to be logical solution to break the therapeutic ceiling to improve clinical outcomes in IBD. The combination biologics appear safe and effective; however, the available evidence is limited. Refractory IBD, presence of other immune mediated inflammatory diseases and extra intestinal manifestations are currently the common considerations of combination biologics in IBD. SUMMARY Inflammatory bowel disease is a complex immune mediated disease with diverse clinical presentation and often has a complicated clinical course requiring multidisciplinary management. As the number of targeted therapies increases so does the concern on their safety and efficacy. Combination biologics though may appear to be safe, we need well designed prospective studies for firm conclusions.
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Affiliation(s)
- Sudheer K Vuyyuru
- Department of Gastroenterology and Human nutrition, All India Institute of Medical Sciences, New Delhi, India
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34
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Eronen H, Kolehmainen S, Koffert J, Koskinen I, Oksanen P, Jussila A, Huhtala H, Sipponen T, Ilus T. Combining biological therapies in patients with inflammatory bowel disease: a Finnish multi-centre study. Scand J Gastroenterol 2022; 57:936-941. [PMID: 35238727 DOI: 10.1080/00365521.2022.2045350] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Therapy with two concomitant biologicals targeting different inflammatory pathways has emerged as a new therapy option for treatment refractory inflammatory bowel disease (IBD). Data on the efficacy and safety of dual biological therapy (DBT) are scarce and are investigated in this study. MATERIALS AND METHODS Data on all patients treated with a combination of two biologicals in four Finnish tertiary centres were collected and analysed. Remission was assessed by a physician on the basis of biomarkers, endoscopic evaluation and alleviation of symptoms. RESULTS A total of 16 patients with 22 trials of DBT were included. Fifteen patients had Crohn's disease. The most common combination of DBT was adalimumab (ADA) and ustekinumab (USTE; 36%) with median follow-up of nine months (range 2-31). Altogether seven (32%) patients were in remission at the end of follow-up and in two trials response to DBT was assessed to be partial with the relief of patient symptoms. In a total of four trials DBT reduced the need for corticosteroids. The majority of patients achieving a response to DBT were treated with the combination of ADA and USTE (56%). At the end of follow-up all nine (41%) patients responding to DBT continued treatment. Infection complications occurred in three patients (19%). CONCLUSION DBT is a promising alternative treatment for refractory IBD, and half of our patients benefitted from it. More data on the efficacy and safety of DBT are needed especially in long-term follow up.
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Affiliation(s)
- Heli Eronen
- Department of Gastroenterology, Kanta-Häme Central Hospital, Hämeenlinna, Finland
| | | | - Jukka Koffert
- Department of Gastroenterology, Turku University Hospital, Turku, Finland
| | - Inka Koskinen
- Department of Internal Medicine, Central Finland Central Hospital, Jyväskylä, Finland
| | - Pia Oksanen
- Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, and University of Tampere, Tampere, Finland
| | - Airi Jussila
- Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland
| | - Heini Huhtala
- Faculty of Social Sciences, Tampere University, Tampere, Finland
| | - Taina Sipponen
- Gastroenterology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Tuire Ilus
- Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland
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35
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Kabbani M, Mboyo Mpita G, Benhadou F. Ustekinumab plus dupilumab in the treatment of concomitant psoriasis and prurigo nodularis. J Eur Acad Dermatol Venereol 2022; 36:e1050-e1051. [PMID: 35857380 DOI: 10.1111/jdv.18445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Mariam Kabbani
- Department of Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Greta Mboyo Mpita
- Department of Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Farida Benhadou
- Department of Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
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36
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AlAmeel T, Al Sulais E, Raine T. Methotrexate in inflammatory bowel disease: A primer for gastroenterologists. Saudi J Gastroenterol 2022; 28:250-260. [PMID: 35042318 PMCID: PMC9408741 DOI: 10.4103/sjg.sjg_496_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/24/2021] [Accepted: 11/22/2021] [Indexed: 11/06/2022] Open
Abstract
Methotrexate is an antineoplastic agent that is also used at lower doses for anti-inflammatory properties. Along with thiopurines (azathioprine and 6-mercaptopurine), it has historically been an important part of pharmacological treatment for patients with inflammatory bowel disease. Despite an increase in therapeutic options, these immunomodulators continue to play important roles in the management of inflammatory bowel disease, used either as a monotherapy in mild to moderate cases or in combination with monoclonal antibodies to prevent immunogenicity and maintain efficacy. In light of data linking the use of thiopurines with the risk of malignancies, methotrexate has regained attention as a potential alternative. In this article, we review data on the pharmacology, safety, and efficacy of methotrexate and discuss options for the positioning of methotrexate alone, or in combination, in therapeutic algorithms for Crohn's disease and ulcerative colitis.
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Affiliation(s)
- Turki AlAmeel
- Department of Medicine, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Eman Al Sulais
- Division of Gastroenterology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
| | - Tim Raine
- Division of Gastroenterology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
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37
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Kataria J, Kerr J, Lourenssen SR, Blennerhassett MG. Nintedanib regulates intestinal smooth muscle hyperplasia and phenotype in vitro and in TNBS colitis in vivo. Sci Rep 2022; 12:10275. [PMID: 35715562 PMCID: PMC9206006 DOI: 10.1038/s41598-022-14491-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 06/08/2022] [Indexed: 02/07/2023] Open
Abstract
Chronic inflammation of the human intestine in Crohn’s disease (CD) causes bowel wall thickening, which typically progresses to stricturing and a recurrent need for surgery. Current therapies have limited success and CD remains idiopathic and incurable. Recent evidence shows a key role of intestinal smooth muscle cell (ISMC) hyperplasia in stricturing, which is not targeted by current anti-inflammatory therapeutics. However, progression of idiopathic pulmonary fibrosis, resembling CD in pathophysiology, is controlled by the tyrosine kinase inhibitors nintedanib (NIN) or pirfenidone, and we investigated these drugs for their effect on ISMC. In a culture model of rat ISMC, NIN inhibited serum- and PDGF-BB-stimulated growth and cell migration, and promoted the differentiated phenotype, while increasing secreted collagen. NIN did not affect signaling through PDGF-Rβ or NFκB but did inhibit cytokine-induced expression of the pro-inflammatory cytokines IL-1β and TNFα, supporting a transcriptional level of control. In TNBS-induced colitis in mice, which resembles CD, NIN decreased ISMC hyperplasia as well as expression of TNFα and IL-1β, without effect in control animals. NIN also inhibited growth of human ISMC in response to human serum or PDGF-BB, which further establishes a broad range of actions of NIN that support further trial in human IBD.
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Affiliation(s)
- Jay Kataria
- Gastrointestinal Diseases Research Unit, Department of Medicine, GIDRU Wing, Kingston General Hospital, Queen's University, Kingston, ON, K7L 2V7, Canada
| | - Jack Kerr
- Gastrointestinal Diseases Research Unit, Department of Medicine, GIDRU Wing, Kingston General Hospital, Queen's University, Kingston, ON, K7L 2V7, Canada
| | - Sandra R Lourenssen
- Gastrointestinal Diseases Research Unit, Department of Medicine, GIDRU Wing, Kingston General Hospital, Queen's University, Kingston, ON, K7L 2V7, Canada
| | - Michael G Blennerhassett
- Gastrointestinal Diseases Research Unit, Department of Medicine, GIDRU Wing, Kingston General Hospital, Queen's University, Kingston, ON, K7L 2V7, Canada.
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Raine T, Danese S. Breaking Through the Therapeutic Ceiling: What Will It Take? Gastroenterology 2022; 162:1507-1511. [PMID: 34995533 DOI: 10.1053/j.gastro.2021.09.078] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 07/22/2021] [Accepted: 09/07/2021] [Indexed: 12/22/2022]
Abstract
Outcomes for patients starting a new treatment for inflammatory bowel disease are characterized by uncertainty of treatment response. Although it is natural to hope that new treatments will be characterized by better efficacy, remission is still far from a universal experience for patients living with inflammatory bowel disease. At times, an apparent "glass ceiling" appears to constrain progress toward a goal of maximal long-term health care-related quality of life for all. There are a number of areas that can and should be addressed if we are to make significant progress. These range from improved early diagnosis and initial management through better treatment stratification and response monitoring, to improvements in clinical trial design and selection of drugs in combination therapies. In this article, we discuss the steps required in all of these areas to make best use of new therapeutic options and shatter the glass ceiling.
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Affiliation(s)
- Tim Raine
- Department of Gastroenterology, Cambridge University Hospitals, Cambridge, United Kingdom.
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milan, Italy
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39
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Dual biologic therapy with Vedolizumab and Ustekinumab for refractory Crohn's disease in children. Eur J Gastroenterol Hepatol 2022; 34:372-374. [PMID: 34034281 DOI: 10.1097/meg.0000000000002203] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
There is a paucity of treatment options for patients who have failed multiple biologics. A drawback of biologic therapies is their selectivity in targeting a single pathway. We report the use of dual biologic therapy with vedolizumab and ustekinumab for three highly refractory patients who previously failed both of these medications as monotherapy. The dual biologic therapy led to the closure of a recto-vaginal fistula and restoration of continuity after takedown of a stoma.
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40
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Peterson AR, Hilley P, De Cruz P. Combination Tofacitinib and Calcineurin Inhibitor in the Management of Treatment-Refractory Ulcerative Colitis May Be Effective, But Is It Necessary? Inflamm Bowel Dis 2022; 28:e46. [PMID: 35045169 DOI: 10.1093/ibd/izab356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Affiliation(s)
| | | | - Peter De Cruz
- IBD Service, Austin Health, Melbourne, Australia.,Department of Medicine, Austin Academic Centre, University of Melbourne, Melbourne, Australia
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41
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Ahmed W, Galati J, Kumar A, Christos PJ, Longman R, Lukin DJ, Scherl E, Battat R. Dual Biologic or Small Molecule Therapy for Treatment of Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2022; 20:e361-e379. [PMID: 33798711 DOI: 10.1016/j.cgh.2021.03.034] [Citation(s) in RCA: 87] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 03/27/2021] [Accepted: 03/29/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS We conducted a systematic review and meta-analysis to summarize emerging data on the safety and effectiveness of dual biologic therapy in combination or with tofacitinib in patients with refractory inflammatory bowel disease (IBD). METHODS Through a systematic search of multiple electronic databases through November 9, 2020, we identified cohort studies or case series (>10 patients) reporting the safety and effectiveness of simultaneous use of biologic agents in combination or with tofacitinib in patients with IBD. Rates of adverse events, clinical remission, and endoscopic remission were synthesized using pooled data, and we identified factors associated with successful dual therapy. RESULTS We identified 30 studies reporting 288 trials of dual biologic or small molecule therapy in 279 patients (76% Crohn's disease; median duration of treatment 24 weeks (IQR25-IQR75 1332)). The main indications for dual therapy included medically refractory IBD (81%) and concurrent extra-intestinal manifestations or rheumatologic disease (12%). The most common combinations of dual therapy included tumor necrosis factor-α antagonists & anti-integrins (48%), ustekinumab & anti-integrins (19%); 61% of patients had previously failed at least one of the two therapies used in combination. Over a median follow-up of 32 weeks (IQR25-IQR75 24-52), pooled rates of adverse and serious adverse events were 31% (95% CI, 13%-54%) and 6.5% (95% CI, 2.1%-13.1%); pooled rates of clinical and endoscopic remission were 59% (95% CI, 42%-74%), and 34% (95% CI, 23%-46%), respectively. 12% (95% CI, 4%-24%) of patients required surgery. Rates of success were higher in patients on dual therapy due to EIM. Heterogeneity was not significant for endoscopic response (P = .88, I2 = 0%), endoscopic remission (P = .44, I2 = 0%), and malignancy (P = .87, I2 = 0%). However, significant heterogeneity existed for other outcomes. CONCLUSIONS Dual biologic or small molecule therapy may be a possible option in highly selected, refractory IBD patients at specialized centers. Higher quality combination of therapies with a significant improvement in the quality of data is required prior to more widespread use.
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Affiliation(s)
- Waseem Ahmed
- Jill Roberts Center for Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Jonathan Galati
- Department of Medicine, New York University School of Medicine, New York, New York
| | - Anand Kumar
- Jill Roberts Center for Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medical College, New York, New York; Division of Gastroenterology and Hepatology, Department of Medicine, Lenox Hill Hospital, New York, New York
| | - Paul J Christos
- Division of Biostatistics, Department of Population Health Sciences, Weill Cornell Medical College, New York, New York
| | - Randy Longman
- Jill Roberts Center for Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Dana J Lukin
- Jill Roberts Center for Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Ellen Scherl
- Jill Roberts Center for Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Robert Battat
- Jill Roberts Center for Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medical College, New York, New York.
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Mas EB, Calvo XC. Selecting the Best Combined Biological Therapy for Refractory Inflammatory Bowel Disease Patients. J Clin Med 2022; 11:1076. [PMID: 35207347 PMCID: PMC8877715 DOI: 10.3390/jcm11041076] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/13/2022] [Accepted: 02/16/2022] [Indexed: 02/07/2023] Open
Abstract
Current medical treatment for inflammatory bowel disease (IBD) does not achieve 100% response rates, and a subset of refractory and severely ill patients have persistent active disease after being treated with all possible drug alternatives. The combination of two biological therapies (CoT) seems a reasonable alternative, and has been increasingly tested in very difficult cases. The present review suggests that CoT seems to be safe and effective for refractory and severely ill IBD patients. Ustekinumab plus vedolizumab and vedolizumab plus anti-TNF were the most used CoTs for Crohn's disease. For ulcerative colitis, the most used CoTs were vedolizumab plus anti-TNF and vedolizumab plus tofacitinib. The aforesaid CoTs have shown good efficacy and few adverse events have been reported.
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Affiliation(s)
- Eduard Brunet Mas
- Servei Aparell Digestiu, Hospital Universitari Parc Taulí, 08208 Sabadell, Spain;
- Departament de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
- CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Xavier Calvet Calvo
- Servei Aparell Digestiu, Hospital Universitari Parc Taulí, 08208 Sabadell, Spain;
- Departament de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
- CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain
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43
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Ahmed W. Breaking the Therapeutic Ceiling: Dual Biologic or Small Molecule Therapy for Refractory Inflammatory Bowel Disease. CROHN'S & COLITIS 360 2022; 4:otac005. [PMID: 36777549 PMCID: PMC9802154 DOI: 10.1093/crocol/otac005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Waseem Ahmed
- University of Colorado Crohn’s and Colitis Center, Aurora, Colorado, USA,Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, Colorado, USA,Address correspondence to: Waseem Ahmed, MD, University of Colorado Crohn’s and Colitis Center, 1635 Aurora Court, Anschutz Outpatient Pavilion, 6th Floor, Aurora, CO 80045, USA ()
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44
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Robinson G, Pineda-Torra I, Ciurtin C, Jury EC. Lipid metabolism in autoimmune rheumatic disease: implications for modern and conventional therapies. J Clin Invest 2022; 132:e148552. [PMID: 35040437 PMCID: PMC8759788 DOI: 10.1172/jci148552] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Suppressing inflammation has been the primary focus of therapies in autoimmune rheumatic diseases (AIRDs), including rheumatoid arthritis and systemic lupus erythematosus. However, conventional therapies with low target specificity can have effects on cell metabolism that are less predictable. A key example is lipid metabolism; current therapies can improve or exacerbate dyslipidemia. Many conventional drugs also require in vivo metabolism for their conversion into therapeutically beneficial products; however, drug metabolism often involves the additional formation of toxic by-products, and rates of drug metabolism can be heterogeneous between patients. New therapeutic technologies and research have highlighted alternative metabolic pathways that can be more specifically targeted to reduce inflammation but also to prevent undesirable off-target metabolic consequences of conventional antiinflammatory therapies. This Review highlights the role of lipid metabolism in inflammation and in the mechanisms of action of AIRD therapeutics. Opportunities for cotherapies targeting lipid metabolism that could reduce immunometabolic complications and potential increased cardiovascular disease risk in patients with AIRDs are discussed.
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Affiliation(s)
- George Robinson
- Centre for Rheumatology Research
- Centre for Adolescent Rheumatology Research, and
| | - Ines Pineda-Torra
- Centre for Cardiometabolic and Vascular Science, Division of Medicine, University College London, London, United Kingdom
| | - Coziana Ciurtin
- Centre for Rheumatology Research
- Centre for Adolescent Rheumatology Research, and
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45
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Revés J, Ungaro RC, Torres J. Unmet needs in inflammatory bowel disease. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2022; 2:100070. [PMID: 34988431 PMCID: PMC8710990 DOI: 10.1016/j.crphar.2021.100070] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/16/2021] [Accepted: 11/22/2021] [Indexed: 12/15/2022] Open
Abstract
Despite the recent developments in the diagnosis and management of inflammatory bowel diseases (IBD), patients still suffer from disabling bowel symptoms and significant disease complications and many questions remain to improve their care. IBD is a chronic disease, whose management could be divided into the five different stages of chronic diseases, ranging from the pre-treatment evaluation phase to the induction therapy, maintenance therapy, monitor and re-establishment of control and the cessation of the disease. Reconciling these phases with the current unmet needs in IBD could help tailor priorities for research. In this review, some of the unanswered questions in the management of both Crohn’s Disease and Ulcerative Colitis will be addressed, by following this paradigm of chronic diseases’ management.
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Affiliation(s)
- Joana Revés
- Division of Gastroenterology, Surgical Department, Hospital Beatriz Ângelo, Loures, Portugal
| | - Ryan C Ungaro
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Joana Torres
- Division of Gastroenterology, Surgical Department, Hospital Beatriz Ângelo, Loures, Portugal.,Faculdade de Medicina, Universidade de Lisboa, Portugal
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46
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Alayo QA, Fenster M, Altayar O, Glassner KL, Llano E, Clark-Snustad K, Patel A, Kwapisz L, Yarur A, Cohen BL, Ciorba MA, Thomas D, Lee SD, Loftus EV, Fudman DI, Abraham BP, Colombel JF, Deepak P. Systematic Review With Meta-analysis: Safety and Effectiveness of Combining Biologics and Small Molecules in Inflammatory Bowel Disease. CROHN'S & COLITIS 360 2022; 4:otac002. [PMID: 35310082 PMCID: PMC8924906 DOI: 10.1093/crocol/otac002] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Indexed: 12/22/2022] Open
Abstract
Background Combining biologics and small molecules could potentially overcome the plateau of drug efficacy in inflammatory bowel disease (IBD). We conducted a systematic review and meta-analysis to assess the safety and effectiveness of dual biologic therapy (DBT), or small molecule combined with a biologic therapy (SBT) in IBD patients. Methods We searched MEDLINE, EMBASE, Scopus, Web of Science, Cochrane Database of Systematic Reviews, and Clinical trials.gov until November 3, 2020, including studies with 2 or more IBD patients on DBT or SBT. Main outcome was safety assessed as pooled rates of adverse events (AEs) and serious AEs (SAEs) for each combination. Effectiveness was reported as pooled rates of clinical, endoscopic, and/or radiographic response and remission. The certainty of evidence was rated according to the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) framework. Results Of the 3688 publications identified, 13 studies (1 clinical trial, 12 observational studies) involving 266 patients on 7 different combinations were included. Median number of prior biologics ranged from 0 to 4, and median duration of follow-up was 16-68 weeks. Most common DBT and SBT were vedolizumab (VDZ) with anti-tumor necrosis factor (aTNF, n = 56) or tofacitinib (Tofa, n = 57), respectively. Pooled rates of SAE for these were 9.6% (95% confidence interval [CI], 1.5-21.4) for VDZ-aTNF and 1.0% (95% CI, 0.0-7.6) for Tofa-VDZ. The overall certainty of evidence was very low due to the observational nature of the studies, and very serious imprecision and inconsistency. Conclusions DBT or SBT appears to be generally safe and may be effective in IBD patients, but the evidence is very uncertain.
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Affiliation(s)
- Quazim A Alayo
- Department of Internal Medicine, St. Luke’s Hospital, St. Louis, Missouri, USA
- Division of Gastroenterology and Inflammatory Bowel Diseases Centre, Washington University in Saint Louis School of Medicine, St. Louis, Missouri, USA
| | - Marc Fenster
- Division of Gastroenterology, Albert Einstein College of Medicine, Montefiore Medical Centre, Bronx, New York, USA
| | - Osama Altayar
- Division of Gastroenterology, Washington University in Saint Louis School of Medicine, St. Louis, Missouri, USA
| | - Kerri L Glassner
- Division of Gastroenterology and Hepatology, Houston Methodist Hospital, Houston, Texas, USA
| | - Ernesto Llano
- Division of Digestive and Liver Diseases, University of Texas Southwestern, Dallas, Texas, USA
| | - Kindra Clark-Snustad
- Division of Gastroenterology, University of Washington Medical Centre, Seattle, Washington, USA
| | - Anish Patel
- Division of Gastroenterology, Brooke Army Medical Centre, Fort Sam Houston, Texas, USA
| | - Lukasz Kwapisz
- Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas, USA
| | - Andres J Yarur
- Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Benjamin L Cohen
- Department of Gastroenterology, Hepatology, and Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Matthew A Ciorba
- Division of Gastroenterology and Inflammatory Bowel Diseases Centre, Washington University in Saint Louis School of Medicine, St. Louis, Missouri, USA
| | - Deborah Thomas
- Bernard Becker Medical Library, Washington University in Saint Louis, St. Louis, Missouri, USA
| | - Scott D Lee
- Division of Gastroenterology, University of Washington Medical Centre, Seattle, Washington, USA
| | - Edward V Loftus
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
| | - David I Fudman
- Division of Digestive and Liver Diseases, University of Texas Southwestern, Dallas, Texas, USA
| | - Bincy P Abraham
- Division of Gastroenterology and Hepatology, Houston Methodist Hospital, Houston, Texas, USA
| | - Jean-Frederic Colombel
- Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Parakkal Deepak
- Division of Gastroenterology and Inflammatory Bowel Diseases Centre, Washington University in Saint Louis School of Medicine, St. Louis, Missouri, USA
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47
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Yang Q, Chen L, Feng L, Liu C, Fang L, Liu Z, Sun X. Success of Cyclosporin and Tofacitinib Combination Therapy in a Patient With Severe Steroid-refractory Ulcerative Colitis. Inflamm Bowel Dis 2021; 27:e157-e158. [PMID: 34398196 DOI: 10.1093/ibd/izab181] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
At present, the conventional therapies for acute severe ulcerative colitis (ASUC) mainly include corticosteroids, cyclosporin, and biological agents. However, the treatment of patients with severe steroid-refractory ulcerative colitis remains a serious challenge to clinicians. This study reports a case of steroid-refractory ASUC treated with cyclosporin combined with tofacitinib after treatment failure with infliximab.
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Affiliation(s)
- Qinglu Yang
- Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Liang Chen
- Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Lijin Feng
- Department of Pathology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Changqin Liu
- Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Leilei Fang
- Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Zhanju Liu
- Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Xiaomin Sun
- Department of Gastroenterology, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
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48
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Yau YY, Wasinger VC, Hirten RP, Chuang E, Huntsman M, Stylli J, Shimizu J, Yajnik V, Smith J, Lee SN, Singh S, Wahl C, Leong RW, Sands BE. Current Trends in IBD-Development of Mucosal-Based Biomarkers and a Novel Minimally Invasive Recoverable Sampling System. Inflamm Bowel Dis 2021; 27:S17-S24. [PMID: 34791290 PMCID: PMC9214562 DOI: 10.1093/ibd/izab179] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Indexed: 12/16/2022]
Abstract
Despite recent developments in therapy for inflammatory bowel diseases (IBDs), there have been limited advances in diagnostic tools available to aid in disease management. A growing body of evidence suggests that there are important host-microbe interactions at the mucosal interface that modulate the inflammatory response in patients with IBD. Additionally, the importance of mucosal integrity and its disruption appears to be important in the pathophysiology and perpetuation of the disease. The ability to characterize this interface may provide valuable information for both disease monitoring and identification of new treatment targets. Endoscopy remains the primary tool for disease monitoring, and mucosal healing is the primary therapeutic target in IBD treatment. However, establishing mucosal healing requires repetitive endoscopic procedures, and endoscopy is limited by factors such as invasiveness, cost, and risk of adverse events. Moreover, the use of a bowel preparation for colonoscopies alters the mucus layer and thus perturbs evaluation of the host-microbe interaction. Stool sampling may also be inaccurate because it reflects the end state of metabolites and proteins, failing to take into account the degradation or alteration of substrates of interest by bacterial proteases and other enzymes during passage through the colon. A novel sampling capsule, called the Recoverable Sampling System (RSS), is being developed as a complementary tool to colonoscopy. The RSS is intended to be a platform for noninvasive autonomous sampling, preservation, handling, and storage of analytes of interest found in the gastrointestinal fluids. A proprietary preservative contained within the chambers of the capsule has been developed to stabilize DNA and proteins for ex vivo microbiome and metabolomics analyses. Surrogate markers such as SPP24 and GUCA2a have been identified to correlate with gut health, intestinal permeability, and inflammation and could be locally sampled by the RSS. The potential clinical utility of an RSS device is broad and would likely be able to guide therapy by allowing for more frequent disease monitoring, aiding in disease characterization, and facilitating in the identification of novel therapeutic targets.
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Affiliation(s)
| | | | - Robert P Hirten
- Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Emil Chuang
- Address correspondence to: Emil Chuang, MB, BS, Progenity, Inc, San Diego, CA, USA ()
| | | | - Jack Stylli
- Georgetown University, School of Medicine, Washington D.C., USA
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49
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Taberner Bonastre P, Torres Vicente G, Cano-Marron M, Sese Abizanda E, Volta Pardo TD, Schoenenberger-Arnaiz JA. A patient with ulcerative colitis treated with a combination of vedolizumab and tofacitinib. Eur J Hosp Pharm 2021; 28:353-355. [PMID: 33495165 PMCID: PMC8552135 DOI: 10.1136/ejhpharm-2020-002437] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 01/03/2021] [Accepted: 01/12/2021] [Indexed: 11/04/2022] Open
Abstract
Ulcerative colitis (UC) is an inflammatory bowel disease of autoimmune origin with an estimated prevalence in Spain of 0.39%. Current treatments for UC do not achieve high long-term efficacy. Treatment recommendations in moderate and severe disease involve drugs, but when these options fail, the alternatives are scarce, and surgery is intended to be reserved for the last option. We present the case of a 48-year-old male patient with UC for 23 years, who had failed several lines of treatment. The patient started combined therapy with tofacitinib and vedolizumab. These drugs have different mechanisms of action, achieving an immune response and reducing gastrointestinal inflammation. The patient's disease symptoms improved 11 months after starting this treatment, and he is now entirely asymptomatic. Analytical parameters related to the disease have also shown improvement, and the patient has so far avoided the need for surgical intervention.
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Affiliation(s)
| | | | | | - Eva Sese Abizanda
- Gastroenterology, Hospital Universitari Arnau de Vilanova, Lleida, Catalunya, Spain
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50
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Raine T, Verstockt B, Kopylov U, Karmiris K, Goldberg R, Atreya R, Burisch J, Burke J, Ellul P, Hedin C, Holubar SD, Katsanos K, Lobaton T, Schmidt C, Cullen G. ECCO Topical Review: Refractory Inflammatory Bowel Disease. J Crohns Colitis 2021; 15:1605-1620. [PMID: 34160593 DOI: 10.1093/ecco-jcc/jjab112] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Inflammatory bowel disease is a chronic disease with variable degrees of extent, severity, and activity. A proportion of patients will have disease that is refractory to licensed therapies, resulting in significant impairment in quality of life. The treatment of these patients involves a systematic approach by the entire multidisciplinary team, with particular consideration given to medical options including unlicensed therapies, surgical interventions, and dietetic and psychological support. The purpose of this review is to guide clinicians through this process and provide an accurate summary of the available evidence for different strategies.
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Affiliation(s)
- Tim Raine
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Bram Verstockt
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
- Department of Chronic Diseases and Metabolism, TARGID - IBD, KU Leuven, Leuven, Belgium
| | - Uri Kopylov
- Department of Gastroenterology, Sheba Medical Center, Ramat Gan, Israel
- Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | | | - Rimma Goldberg
- Department of Gastroenterology, Monash Health and School of Clinical Sciences, Monash University, Melbourne, VIC, Australia
| | - Raja Atreya
- Department of Medicine 1, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Johan Burisch
- Gastrounit, Medical Division, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
| | - John Burke
- Colorectal and General Surgery, Beaumont Hospital, Dublin, Ireland
| | - Pierre Ellul
- Department of Medicine, Division of Gastroenterology, Mater Dei Hospital, Msida, Malta
| | - Charlotte Hedin
- Karolinska Institutet, Department of Medicine Solna, Stockholm, Sweden
- Karolinska University Hospital, Gastroenterology Unit, Department of Gastroenterology, Dermatovenereology and Rheumatology, Stockholm, Sweden
| | - Stefan D Holubar
- Department of Colon & Rectal Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - Konstantinos Katsanos
- Department of Gastroenterology and Hepatology, University and Medical School of Ioannina, Ioannina, Greece
| | - Triana Lobaton
- Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium
| | - Carsten Schmidt
- Medical Faculty of the Friedrich Schiller University, Jena, Germany
| | - Garret Cullen
- Centre for Colorectal Disease, St Vincent's University Hospital and School of Medicine, University College Dublin, Gastroenterology, Dublin, Ireland
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