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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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Mou Y, Wen S, Wang Y, Zhao Y, Li YP, Sha HK, Gui LJ, Jiang ZY, Xu XM. Discovery of Novel Tofacitinib-ADTOH Molecular Hybridization Derivatives for the Treatment of Ulcerative Colitis. Antioxidants (Basel) 2025; 14:325. [PMID: 40227328 PMCID: PMC11939234 DOI: 10.3390/antiox14030325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 02/28/2025] [Accepted: 03/03/2025] [Indexed: 04/15/2025] Open
Abstract
The treatment of ulcerative colitis (UC) has been a major medical challenge due to the lack of safe and effective drugs. Molecular hybridization is a promising strategy for the development of drugs with pleiotropic activity, which has been demonstrated in a wide range of diseases. Tofacitinib has exhibited significant effects on the remission of UC, but a series of adverse effects have occurred during its clinical application. Herein, we propose to utilize a molecular hybridization strategy to link tofacitinib with a cytoprotective H2S donor (ADTOH) to obtain a series of hybridized molecules ZX-4C~ZX-6C. Among them, ZX-4C exhibited the best performance in the H2S release rate and the cytoprotective effects against dextran sulfate sodium (DSS)-induced injury. The in vivo studies showed that ZX-4C could effectively alleviate DSS-induced colitis by enhancing oxidative stress defense and reducing the inflammatory response, demonstrating that it is more potent than the parent drugs. The data from the present study support that this molecular hybridization strategy provides a promising avenue for the treatment of UC.
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Affiliation(s)
- Yi Mou
- College of Pharmacy and Chemistry & Chemical Engineering, Taizhou University, Taizhou 225300, China; (Y.M.); (S.W.); (Y.W.); (Y.Z.); (Y.-P.L.); (H.-K.S.); (L.-J.G.)
| | - Shuai Wen
- College of Pharmacy and Chemistry & Chemical Engineering, Taizhou University, Taizhou 225300, China; (Y.M.); (S.W.); (Y.W.); (Y.Z.); (Y.-P.L.); (H.-K.S.); (L.-J.G.)
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
| | - Yan Wang
- College of Pharmacy and Chemistry & Chemical Engineering, Taizhou University, Taizhou 225300, China; (Y.M.); (S.W.); (Y.W.); (Y.Z.); (Y.-P.L.); (H.-K.S.); (L.-J.G.)
| | - Yao Zhao
- College of Pharmacy and Chemistry & Chemical Engineering, Taizhou University, Taizhou 225300, China; (Y.M.); (S.W.); (Y.W.); (Y.Z.); (Y.-P.L.); (H.-K.S.); (L.-J.G.)
| | - Ying-Ping Li
- College of Pharmacy and Chemistry & Chemical Engineering, Taizhou University, Taizhou 225300, China; (Y.M.); (S.W.); (Y.W.); (Y.Z.); (Y.-P.L.); (H.-K.S.); (L.-J.G.)
| | - Hong-Kai Sha
- College of Pharmacy and Chemistry & Chemical Engineering, Taizhou University, Taizhou 225300, China; (Y.M.); (S.W.); (Y.W.); (Y.Z.); (Y.-P.L.); (H.-K.S.); (L.-J.G.)
| | - Li-Juan Gui
- College of Pharmacy and Chemistry & Chemical Engineering, Taizhou University, Taizhou 225300, China; (Y.M.); (S.W.); (Y.W.); (Y.Z.); (Y.-P.L.); (H.-K.S.); (L.-J.G.)
| | - Zheng-Yu Jiang
- Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
| | - Xiang-Ming Xu
- College of Pharmacy and Chemistry & Chemical Engineering, Taizhou University, Taizhou 225300, China; (Y.M.); (S.W.); (Y.W.); (Y.Z.); (Y.-P.L.); (H.-K.S.); (L.-J.G.)
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Yan JW, Nie M, Zhang H, Liu YM, Tang FS. Strengths, weaknesses, opportunities, and threats analysis of combination therapy for inflammatory bowel disease. World J Gastroenterol 2025; 31:100607. [PMID: 40061596 PMCID: PMC11886040 DOI: 10.3748/wjg.v31.i9.100607] [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: 08/21/2024] [Revised: 01/12/2025] [Accepted: 01/18/2025] [Indexed: 02/18/2025] Open
Abstract
Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, manifests as a chronic, recurrent, and refractory intestinal inflammatory condition significantly impacting patients' quality of life. Despite ongoing research, its etiology and pathogenesis remain incompletely understood. Recent advancements in medical research highlight the critical role of drug combination therapies in managing IBD. This paper employs the strengths, weaknesses, opportunities, and threats framework to evaluate the four strategic elements (strengths, weaknesses, opportunities, and threats) pertaining to combination therapies for IBD. Among the strengths, the paper underscores the efficacy of multi-targeted strategies, the advancement of personalized medicine, and the mitigation of drug resistance. Nonetheless, the analysis identifies significant weaknesses, including the prohibitive cost of treatment, issues with patient compliance, and the necessity for comprehensive long-term safety data. The paper also delineates opportunities to augment therapeutic success through the incorporation of biomarkers, the application of artificial intelligence, and extensive international collaborative efforts. In contrast, the paper does not shy away from addressing the threats, which include the potential for therapeutic resistance and the logistical challenges inherent in global therapy deployment. These initiatives aim to refine future therapeutic practices, fostering safer, more effective, and personalized treatment paradigms for IBD patients.
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Affiliation(s)
- Jia-Wang Yan
- Department of Clinical Pharmacy, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
- Key Laboratory of Basic Pharmacology of Guizhou Province and School of Pharmacy, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
| | - Mei Nie
- Department of Clinical Pharmacy, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
- Key Laboratory of Basic Pharmacology of Guizhou Province and School of Pharmacy, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
| | - Hang Zhang
- Department of Clinical Pharmacy, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
- Key Laboratory of Basic Pharmacology of Guizhou Province and School of Pharmacy, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
| | - Yan-Miao Liu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
- Key Laboratory of Basic Pharmacology of Guizhou Province and School of Pharmacy, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
- The First Clinical Institute, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
| | - Fu-Shan Tang
- Department of Clinical Pharmacy, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
- Key Laboratory of Basic Pharmacology of Guizhou Province and School of Pharmacy, Zunyi Medical University, Zunyi 563006, Guizhou Province, China
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Yang JC, Janssen EM, Wallace MJ, Sheahan A, Lynch J, Bewtra M, Marko M, Johnson FR, Bozzi LM. Quantifying Patient Preferences for Risk Tolerance With Novel Dual Biologic Therapies for Inflammatory Bowel Disease. Am J Gastroenterol 2025:00000434-990000000-01620. [PMID: 40243385 DOI: 10.14309/ajg.0000000000003397] [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: 10/17/2024] [Accepted: 02/24/2025] [Indexed: 04/18/2025]
Abstract
INTRODUCTION Many patients with inflammatory bowel disease (IBD) experience treatment failures despite availability of effective advanced biologic and small-molecule therapies with differing mechanisms of action. Dual biologic therapy (DBT) is being explored to improve efficacy outcomes and address unmet needs in this difficult-to-treat population. This study aimed to understand patient preferences for DBT efficacy and risk tolerance. METHODS Built on evidence from existing treatment-preference studies, a focused discrete-choice experiment (DCE) was developed to measure preferences for treatment type, chance of remission, and risk of serious infection. Individuals with a physician-verified diagnosis of Crohn's disease or ulcerative colitis who had failed or were taking advanced therapy were recruited through an IBD registry. DCE responses were analyzed using a fully correlated random parameters logit model. RESULTS The DCE survey was completed by 280 respondents. The majority of respondents were White, female; had been previously hospitalized for IBD; and were receiving biologic monotherapy for their IBD disease. There was no meaningful difference in preference for DBT or monotherapy (P = 0.25), while there was strong preference to avoid corticosteroids (P < 0.001). To improve from a 50% to 70% in chance of remission, respondents would accept up to a 17.5% (95% confidence interval 17.0%-18.0%) risk of serious infection. DISCUSSION The findings suggest that patients prefer safe and efficacious treatments and DBT may be an acceptable option for those who have failed an advanced therapy for IBD. We demonstrate the value of building on existing evidence and designing efficient DCE studies to address knowledge gaps to improve IBD care.
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Affiliation(s)
- Jui-Chen Yang
- Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, USA
| | | | - Matthew J Wallace
- Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, USA
| | | | - John Lynch
- Johnson & Johnson, Spring House, PA, USA
| | | | | | - F Reed Johnson
- Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, USA
- University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Yin F, Liu X, He D, Li S, Feng X, Shi Y, Chen M. Comparative Effectiveness of Dual Biologic Therapy and Biologic Small-Molecule Therapy for Refractory Inflammatory Bowel Disease: A Retrospective Single-Center Study. Clin Transl Sci 2025; 18:e70198. [PMID: 40065597 PMCID: PMC11893725 DOI: 10.1111/cts.70198] [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: 11/28/2024] [Revised: 02/27/2025] [Accepted: 03/03/2025] [Indexed: 03/14/2025] Open
Abstract
Patients with refractory inflammatory bowel disease (IBD) face difficulty in the treatment strategy. Combined advanced targeted therapies may obtain higher therapeutic efficacy. However, few studies compare the efficacy and safety of dual biologic therapy (DBT) with biologic small-molecule therapy (BMT) for refractory IBD. We aimed to compare the effectiveness of DBT with BMT. We retrospectively analyzed the data of patients with refractory IBD treated with DBT (n = 22) or BMT (n = 21). The primary outcome was the clinical remission rate at week 12. Secondary outcomes included the clinical response rate, endoscopic response rate, endoscopic remission rate, colectomy rate, and rate of adverse events (AEs) at week 12. At week 12, the clinical remission rates in the DBT group and BMT group were 22.7% and 28.6%, respectively. No statistically significant difference was observed between the two groups (p = 0.661). There were also no statistically significant differences between the DBT group and BMT group in the clinical response rate (68.2% vs. 71.4%, p = 0.817), endoscopic response rate (66.7% vs. 68.8%, p = 1.000), endoscopic remission rate (4.8% vs. 18.8%, p = 0.296) and colectomy rate (4.5% vs. 23.8%, p = 0.167). Two patients (9.5%) in the BMT group and no patients in the DBT group experienced AEs. However, the difference was not statistically significant (p = 0.233). In conclusion, this study revealed that there may be similar effectiveness and safety of DBT and BMT for patients with refractory IBD. Further multi-center, prospective randomized controlled trials are necessary to confirm this conclusion.
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Affiliation(s)
- Fan Yin
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive DiseasesAir Force Military Medical UniversityXi'anChina
- Department of GastroenterologyGuang'an People's HospitalGuang'anChina
| | - Xiaolei Liu
- Department of Medical InsuranceXijing Hospital, Air Force Military Medical UniversityXi'anChina
| | - Dongdong He
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive DiseasesAir Force Military Medical UniversityXi'anChina
| | - Songbo Li
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive DiseasesAir Force Military Medical UniversityXi'anChina
| | - Xin Feng
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive DiseasesAir Force Military Medical UniversityXi'anChina
| | - Yongquan Shi
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive DiseasesAir Force Military Medical UniversityXi'anChina
| | - Min Chen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive DiseasesAir Force Military Medical UniversityXi'anChina
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Battat R, Chang JT, Loftus EV, Sands BE. IBD Matchmaking: Rational Combination Therapy. Clin Gastroenterol Hepatol 2025; 23:469-479. [PMID: 39025253 DOI: 10.1016/j.cgh.2024.05.051] [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: 03/01/2024] [Revised: 05/28/2024] [Accepted: 05/31/2024] [Indexed: 07/20/2024]
Abstract
A growing number of patients with Crohn's disease and ulcerative colitis have disease that is refractory to multiple advanced therapies, have undergone multiple surgeries, and require further treatment options. For this reason, there has been increasing use of multiple simultaneous advanced targeted therapies. Although the knowledge on combined advanced targeted therapy (CATT) in inflammatory bowel disease (IBD) has been largely limited to observational data and early-phase randomized controlled trials, combination of therapies is commonplace in many other diseases. This review discusses conceptual frameworks of CATT in IBD, provides context of combined therapies in other diseases, provides current evidence for CATT in IBD, and projects future applications and positioning of CATT using existing, novel, and orthogonal mechanisms of action. CATT aims to address the need to overcome low efficacy rates and frequent loss of response of current individual therapies. Both treatment exposure and disease duration are major determinants of response to therapy. Identification of safe and effective CATT may impact positioning of this strategy to apply to a broader IBD population.
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Affiliation(s)
- Robert Battat
- Division of Gastroenterology, Centre Hospitalier de l'Université de Montreal, Montreal, Quebec, Canada
| | - John T Chang
- Department of Medicine, University of California San Diego, La Jolla, California; Department of Medicine, Veteran Affairs San Diego Healthcare System, San Diego, California
| | - Edward V Loftus
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Bruce E Sands
- Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York.
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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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Fabisiak A, Caban M, Dudek P, Strigáč A, Małecka-Wojciesko E, Talar-Wojnarowska R. Advancements in dual biologic therapy for inflammatory bowel diseases: efficacy, safety, and future directions. Therap Adv Gastroenterol 2025; 18:17562848241309871. [PMID: 39758970 PMCID: PMC11694300 DOI: 10.1177/17562848241309871] [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: 06/22/2024] [Accepted: 12/10/2024] [Indexed: 01/07/2025] Open
Abstract
Inflammatory bowel diseases (IBDs), primarily encompassing ulcerative colitis and Crohn's disease, represent a challenging spectrum of disorders with a multifaceted pathogenesis. Despite the array of available treatments, a demand for novel therapeutic options persists to achieve remission in a broader patient population. Research findings indicate that relying solely on a single biologic drug may limit future treatment choices, prompting consideration for a more suitable shift from step-up to top-down strategies in certain cases. In the backdrop of advancing drug development, reimagining the application of existing therapies presents a promising avenue. Among these innovative approaches is combination therapy. This review explores the outcomes of recent randomized clinical trials, systematic reviews, and case studies, focusing on dual biologic therapy. It underscores the effectiveness, safety, and tolerability of combining two biologic drugs in IBD, providing insights into a potentially impactful treatment strategy.
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Affiliation(s)
- Adam Fabisiak
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Kopcinskiego 22, Lodz 90-153, Poland
| | - Miłosz Caban
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Patrycja Dudek
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Aleksandra Strigáč
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Ewa Małecka-Wojciesko
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Renata Talar-Wojnarowska
- Department of Digestive Tract Diseases, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
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Hassan SA, Perry C, Carey P, Colohan D, Eltaher MG, Dawoud N, Elkammar M, Rasheed W, Mayne C, Stuffelbeam A, Flomenhoft D, Barrett TA. Dual Biologic Therapy Induces Remission in Refractory Crohn's Disease With Vedolizumab and Ustekinumab. CROHN'S & COLITIS 360 2025; 7:otae080. [PMID: 39867688 PMCID: PMC11759274 DOI: 10.1093/crocol/otae080] [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: 09/06/2024] [Indexed: 01/28/2025] Open
Abstract
Background Despite advancements in the therapeutic armamentarium for Crohn's disease (CD), biologic and small molecule monotherapies are associated with sub-optimal response and remission rates. Utilizing dual biologic therapy (DBT) holds the potential to increase efficacy in the treatment of refractory or partially responsive CD. Evidence pertaining to this strategy remains limited. Methods We retrospectively examined refractory CD patients treated with a combination of ustekinumab and vedolizumab. Outcomes to DBT at week (wk) 52 were compared to monotherapy. The primary outcome constituted corticosteroid-free remission. Secondary outcomes included adverse events, infections, hospitalizations, surgeries, treatment persistence, and disease clearance. Results Sixteen of 21 active refractory CD patients (76%) on DBT achieved disease remission at wk 52. Mucosal healing was observed in 38% (n = 6), biochemical remission in 25% (n = 4), and both clinical and biochemical remission in 38% (n = 6). Of these patients, 50% (n = 8) achieved corticosteroid-free remission. Three patients (37.5%) with corticosteroid-free remission achieved complete disease clearance. Paired median fecal calprotectin decreased from 508 to 118 µg/g (P < .0001). Paired C-reactive protein median decreased from 1.04 to 0.50 mg/dL (P < .0001). Median Harvey Bradshaw Index score reduced from 7 to 2 (P = .003). Endoscopic healing was achieved with a paired simple endoscopic score for CD decrease from 6 to 3 (P = .013). Corticosteroid dependency reduced from 17 to 8 patients discontinuing altogether. Patients still requiring corticosteroids experienced a decrease in average daily dose from 9 to 6 mg (P = .045). At wk 52, 5 patients (24%) did not meet the criteria for remission with 4 requiring CD-related surgical intervention. Mean CD-related hospitalizations reduced from 2.95 ± 2.33 to 0.52 ± 1.12 (P < .001) and surgeries from 1.76 ± 1.3 to 0.14 ± 0.4 (P < .001). Three infections with 1 requiring hospitalization and 1 report of headache were noted. Two patients discontinued DBT. Conclusions Dual biologic therapy with ustekinumab and vedolizumab is a safe and effective strategy to induce disease remission in refractory CD. Large-scale studies are necessary to validate findings in a prospective setting.
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Affiliation(s)
- Syed Adeel Hassan
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Courtney Perry
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Patrick Carey
- Division of Digestive Diseases, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Durham Colohan
- Department of Internal Medicine, University of Kentucky College of Medicine-Northern Kentucky Campus, Highland Heights, KY, USA
| | - Mohamed Gebril Eltaher
- Department of Imaging Physics, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA
| | - Nabila Dawoud
- Department of Internal Medicine, Griffin Hospital, Derby, CT, USA
| | - Mahmoud Elkammar
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Waqas Rasheed
- Department of Medicine, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Casie Mayne
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Amy Stuffelbeam
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Deborah Flomenhoft
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Terrence A Barrett
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky College of Medicine, Lexington, KY, USA
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Yeshi K, Jamtsho T, Wangchuk P. Current Treatments, Emerging Therapeutics, and Natural Remedies for Inflammatory Bowel Disease. Molecules 2024; 29:3954. [PMID: 39203033 PMCID: PMC11357616 DOI: 10.3390/molecules29163954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 08/16/2024] [Accepted: 08/20/2024] [Indexed: 09/03/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic, lifelong disorder characterized by inflammation of the gastrointestinal (GI) tract. The exact etiology of IBD remains incompletely understood due to its multifaceted nature, which includes genetic predisposition, environmental factors, and host immune response dysfunction. Currently, there is no cure for IBD. This review discusses the available treatment options and the challenges they present. Importantly, we examine emerging therapeutics, such as biologics and immunomodulators, that offer targeted treatment strategies for IBD. While many IBD patients do not respond adequately to most biologics, recent clinical trials combining biologics with small-molecule drugs (SMDs) have provided new insights into improving the IBD treatment landscape. Furthermore, numerous novel and specific therapeutic targets have been identified. The high cost of IBD drugs poses a significant barrier to treatment, but this challenge may be alleviated with the development of more affordable biosimilars. Additionally, emerging point-of-care protein biomarkers from serum and plasma are showing potential for enhancing the precision of IBD diagnosis and prognosis. Several natural products (NPs), including crude extracts, small molecules, and peptides, have demonstrated promising anti-inflammatory activity in high-throughput screening (HTS) systems and advanced artificial intelligence (AI)-assisted platforms, such as molecular docking and ADMET prediction. These platforms are advancing the search for alternative IBD therapies derived from natural sources, potentially leading to more affordable and safer treatment options with fewer side effects.
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Affiliation(s)
- Karma Yeshi
- College of Public Health, Medical, and Veterinary Sciences (CPHMVS), James Cook University, Building E4, McGregor Rd, Smithfield, Cairns, QLD 4878, Australia;
- Australian Institute of Tropical Health and Medicine (AITHM), James Cook University, Building E4, McGregor Rd, Smithfield, Cairns, QLD 4878, Australia
| | - Tenzin Jamtsho
- College of Public Health, Medical, and Veterinary Sciences (CPHMVS), James Cook University, Building E4, McGregor Rd, Smithfield, Cairns, QLD 4878, Australia;
- Australian Institute of Tropical Health and Medicine (AITHM), James Cook University, Building E4, McGregor Rd, Smithfield, Cairns, QLD 4878, Australia
| | - Phurpa Wangchuk
- College of Public Health, Medical, and Veterinary Sciences (CPHMVS), James Cook University, Building E4, McGregor Rd, Smithfield, Cairns, QLD 4878, Australia;
- Australian Institute of Tropical Health and Medicine (AITHM), James Cook University, Building E4, McGregor Rd, Smithfield, Cairns, QLD 4878, Australia
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11
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Torres J, Hanauer SB. EXPLORing the Therapeutic Ceiling in Crohn's Disease: Will Combination Pave the Way? Clin Gastroenterol Hepatol 2024; 22:1377-1378. [PMID: 38042231 DOI: 10.1016/j.cgh.2023.11.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Accepted: 11/21/2023] [Indexed: 12/04/2023]
Affiliation(s)
- Joana Torres
- Division of Gastroenterology, Department of Surgery, Hospital Beatriz Ângelo and Hospital da Luz, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Stephen B Hanauer
- Department of Medicine, Northwestern University Feinberg School of Medicine, Evanston, Illinois.
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12
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Li L, Cheng R, Wu Y, Lin H, Gan H, Zhang H. Diagnosis and management of inflammatory bowel disease. J Evid Based Med 2024; 17:409-433. [PMID: 38934234 DOI: 10.1111/jebm.12626] [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: 05/01/2024] [Revised: 06/10/2024] [Accepted: 06/13/2024] [Indexed: 06/28/2024]
Abstract
Inflammatory bowel disease (IBD) is a chronic and relapsing immune-mediated disease of the gastrointestinal tract with a gradually increasing global incidence and prevalence. A prolonged course of IBD leads to a decline in patient quality of life and the creation of a substantial economic burden on society. Owing to the lack of specific diagnostic markers, the diagnosis of IBD still needs a gold standard based on a combination of clinical manifestations, imaging, laboratory, and endoscopic results. Accordingly, the current goals of IBD treatment are to alleviate clinical symptoms and reduce recurrence rates. Therefore, it is imperative to develop a standard set of procedures to diagnose and treat IBD. In this review, we summarize prominent and emerging studies, outline classical and contemporary approaches to diagnosing and managing IBD, and integrate multiple guidelines. Furthermore, we propose the possibility of establishing an early and comprehensive diagnostic workflow and personalized management strategy in the future. We aim to enhance the quality and standardization of diagnostic and treatment procedures for IBD.
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Affiliation(s)
- Lili Li
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Rui Cheng
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Yushan Wu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Hao Lin
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Huatian Gan
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
- The Center of Gerontology and Geriatrics, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Hu Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
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13
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Triantafillidis JK, Zografos CG, Konstadoulakis MM, Papalois AE. Combination treatment of inflammatory bowel disease: Present status and future perspectives. World J Gastroenterol 2024; 30:2068-2080. [PMID: 38681984 PMCID: PMC11045479 DOI: 10.3748/wjg.v30.i15.2068] [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: 12/27/2023] [Revised: 02/20/2024] [Accepted: 03/28/2024] [Indexed: 04/19/2024] Open
Abstract
The treatment of patients with inflammatory bowel disease (IBD), especially those with severe or refractory disease, represents an important challenge for the clinical gastroenterologist. It seems to be no exaggeration to say that in these patients, not only the scientific background of the gastroenterologist is tested, but also the abundance of "gifts" that he should possess (insight, intuition, determination, ability to take initiative, etc.) for the successful outcome of the treatment. In daily clinical practice, depending on the severity of the attack, IBD is treated with one or a combination of two or more pharmaceutical agents. These combinations include not only the first-line drugs (e.g., mesalazine, corticosteroids, antibiotics, etc) but also second- and third-line drugs (immunosuppressants and biologic agents). It is a fact that despite the significant therapeutic advances there is still a significant percentage of patients who do not satisfactorily respond to the treatment applied. Therefore, a part of these patients are going to surgery. In recent years, several small-size clinical studies, reviews, and case reports have been published combining not only biological agents with other drugs (e.g., immunosuppressants or corticosteroids) but also the combination of two biological agents simultaneously, especially in severe cases. In our opinion, it is at least a strange (and largely unexplained) fact that we often use combinations of drugs in a given patient although studies comparing the simultaneous administration of two or more drugs with monotherapy are very few. As mentioned above, there is a timid tendency in the literature to combine two biological agents in severe cases unresponsive to the applied treatment or patients with severe extraintestinal manifestations. The appropriate dosage, the duration of the administration, the suitable timing for checking the clinical and laboratory outcome, as well as the treatment side-effects, should be the subject of intense clinical research shortly. In this editorial, we attempt to summarize the existing data regarding the already applied combination therapies and to humbly formulate thoughts and suggestions for the future application of the combination treatment of biological agents in a well-defined category of patients. We suggest that the application of biomarkers and artificial intelligence could help in establishing new forms of treatment using the available modern drugs in patients with IBD resistant to treatment.
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Affiliation(s)
- John K Triantafillidis
- Inflammatory Bowel Disease Unit, "Metropolitan General" Hospital, Holargos 15562, Attica, Greece
- Hellenic Society for Gastrointestinal Oncology, 354 Iera Odos, Chaidari 12461, Attica, Greece
| | - Constantinos G Zografos
- The 2nd Department of Surgery, University of Athens, School of Medicine, Aretaieion Hospital, Athens 11528, Greece
| | - Manousos M Konstadoulakis
- The 2nd Department of Surgery, University of Athens, School of Medicine, Aretaieion Hospital, Athens 11528, Greece
| | - Apostolos E Papalois
- Unit of Surgical Research and Training, The 2nd Department of Surgery, University of Athens, School of Medicine, Aretaieion Hospital, Athens 11528, Greece
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Wang J, Kang G, Lu H, de Marco A, Yuan H, Feng Z, Gao M, Wang X, Wang H, Zhang X, Wang Y, Zhang M, Wang P, Feng Y, Liu Z, Cao X, Huang H. Novel bispecific nanobody mitigates experimental intestinal inflammation in mice by targeting TNF-α and IL-23p19 bioactivities. Clin Transl Med 2024; 14:e1636. [PMID: 38533646 PMCID: PMC10966562 DOI: 10.1002/ctm2.1636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 03/09/2024] [Indexed: 03/28/2024] Open
Abstract
BACKGROUND Inflammatory bowel diseases (IBDs) pose significant challenges in terms of treatment non-response, necessitating the development of novel therapeutic approaches. Although biological medicines that target TNF-α (tumour necrosis factor-α) have shown clinical success in some IBD patients, a substantial proportion still fails to respond. METHODS We designed bispecific nanobodies (BsNbs) with the ability to simultaneously target human macrophage-expressed membrane TNF-α (hmTNF-α) and IL-23. Additionally, we fused the constant region of human IgG1 Fc (hIgG1 Fc) to BsNb to create BsNb-Fc. Our study encompassed in vitro and in vivo characterization of BsNb and BsNb-Fc. RESULTS BsNb-Fc exhibited an improved serum half-life, targeting capability and effector function than BsNb. It's demonstrated that BsNb-Fc exhibited superior anti-inflammatory effects compared to the anti-TNF-α mAb (infliximab, IFX) combined with anti-IL-12/IL-23p40 mAb (ustekinumab, UST) by Transwell co-culture assays. Notably, in murine models of acute colitis brought on by 2,4,6-trinitrobenzene sulfonic acid（TNBS) and dextran sulphate sodium (DSS), BsNb-Fc effectively alleviated colitis severity. Additionally, BsNb-Fc outperformed the IFX&UST combination in TNBS-induced colitis, significantly reducing colon inflammation in mice with colitis produced by TNBS and DSS. CONCLUSION These findings highlight an enhanced efficacy and improved biostability of BsNb-Fc, suggesting its potential as a promising therapeutic option for IBD patients with insufficient response to TNF-α inhibition. KEY POINTS A bispecific nanobody (BsNb) was created to target TNF-α and IL-23p19, exhibiting high affinity and remarkable stability. BsNb-Fc inhibited the release of cytokines in CD4+T cells during co-culture experiments. BsNb-Fc effectively alleviated colitis severity in mouse model with acute colitis induced by DSS or TNBS, outperforming the IFX&UST combination.
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Affiliation(s)
- Jiewen Wang
- Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and TechnologyTianjin UniversityTianjinChina
| | - Guangbo Kang
- Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and TechnologyTianjin UniversityTianjinChina
| | - Huiying Lu
- Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, The Shanghai Tenth People's HospitalTongji University School of MedicineShanghaiChina
| | - Ario de Marco
- Laboratory for Environmental and Life SciencesUniversity of Nova GoricaNova GoricaSlovenia
| | - Haibin Yuan
- Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and TechnologyTianjin UniversityTianjinChina
| | - Zelin Feng
- Department of Gastroenterology and Hepatology, Tianjin Medical University General HospitalTianjin Medical UniversityTianjinChina
| | - Mengxue Gao
- Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and TechnologyTianjin UniversityTianjinChina
| | - Xiaoli Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General HospitalTianjin Medical UniversityTianjinChina
| | - Huahong Wang
- Department of GastroenterologyPeking University First HospitalBeijingChina
| | - Xiaolan Zhang
- Department of GastroenterologyThe Second Hospital of Hebei Medical UniversityShijiazhuangChina
| | - Yuli Wang
- Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and TechnologyTianjin UniversityTianjinChina
- Tianjin Pharmaceutical Da Ren Tang Group Corporation Limited, Traditional Chinese Pharmacy Research InstituteTianjin Key Laboratory of Quality Control in Chinese MedicineTianjinChina
- State Key Laboratory of Drug Delivery Technology and PharmacokineticsTianjin Institute of Pharmaceutical ResearchTianjinChina
| | - Miao Zhang
- Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and TechnologyTianjin UniversityTianjinChina
- China Resources Biopharmaceutical Company LimitedBeijingChina
| | - Ping Wang
- New Technology R&D DepartmentTianjin Modern Innovative TCM Technology Company LimitedTianjinChina
| | - Yuanhang Feng
- Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and TechnologyTianjin UniversityTianjinChina
| | - Zhanju Liu
- Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, The Shanghai Tenth People's HospitalTongji University School of MedicineShanghaiChina
| | - Xiaocang Cao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General HospitalTianjin Medical UniversityTianjinChina
| | - He Huang
- Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and TechnologyTianjin UniversityTianjinChina
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15
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Yerushalmy-Feler A, Olbjorn C, Kolho KL, Aloi M, Musto F, Martin-de-Carpi J, Lozano-Ruf A, Yogev D, Matar M, Scarallo L, Bramuzzo M, de Ridder L, Kang B, Norden C, Wilson DC, Tzivinikos C, Turner D, Cohen S. Dual Biologic or Small Molecule Therapy in Refractory Pediatric Inflammatory Bowel Disease (DOUBLE-PIBD): A Multicenter Study from the Pediatric IBD Porto Group of ESPGHAN. Inflamm Bowel Dis 2024; 30:159-166. [PMID: 37042978 DOI: 10.1093/ibd/izad064] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Indexed: 04/13/2023]
Abstract
BACKGROUND Current data on dual biologic therapy in children are limited. This multicenter study aimed to evaluate the effectiveness and safety of dual therapy in pediatric patients with inflammatory bowel disease (IBD). METHODS A retrospective study from 14 centers affiliated with the Pediatric IBD Interest and Porto Groups of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. Included were children with IBD who underwent combinations of biologic agents or biologic and small molecule therapy for at least 3 months. Demographic, clinical, laboratory, endoscopic, and imaging data were collected. Adverse events were recorded. RESULTS Sixty-two children (35 Crohn's disease, 27 ulcerative colitis; median age 15.5 [interquartile range, 13.1-16.8] years) were included. They had all failed previous biologic therapies, and 47 (76%) failed at least 2 biologic agents. The dual therapy included an anti-tumor necrosis factor agent and vedolizumab in 30 children (48%), anti-tumor necrosis factor and ustekinumab in 21 (34%) children, vedolizumab and ustekinumab in 8 (13%) children, and tofacitinib with a biologic in 3 (5%) children. Clinical remission was observed in 21 (35%), 30 (50%), and 38 (63%) children at 3, 6, and 12 months, respectively. Normalization of C-reactive protein and decrease in fecal calprotectin to <250 µg/g were achieved in 75% and 64%, respectively, at 12 months of follow-up. Twenty-nine (47%) children sustained adverse events, 8 of which were regarded as serious and led to discontinuation of therapy in 6. CONCLUSIONS Dual biologic therapy may be effective in children with refractory IBD. The potential efficacy should be weighed against the risk of serious adverse events.
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Affiliation(s)
- Anat Yerushalmy-Feler
- Pediatric Gastroenterology Institute, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Christine Olbjorn
- Department of Paediatric and Adolescent Medicine, Akershus University Hospital, Lørenskog, Norway
| | - Kaija-Leena Kolho
- Department of Paediatric Gastroenterology, Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
- Tampere University, Tampere, Finland
| | - Marina Aloi
- Department of Maternal and Child Health, Pediatric Gastroenterology and Liver Unit, Umberto I Hospital, Sapienza University of Rome, Rome, Italy
| | - Francesca Musto
- Department of Maternal and Child Health, Pediatric Gastroenterology and Liver Unit, Umberto I Hospital, Sapienza University of Rome, Rome, Italy
| | - Javier Martin-de-Carpi
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Hospital Sant Joan de Déu, Barcelona, Spain
| | - Ana Lozano-Ruf
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Hospital Sant Joan de Déu, Barcelona, Spain
| | - Dotan Yogev
- Juliet Keiden Institute of Pediatric Gastroenterology and Nutrition, Shaare Zedek Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Manar Matar
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Luca Scarallo
- Gastroenterology and Nutrition Unit, Meyer Children's Hospital, Florence, Italy
| | - Matteo Bramuzzo
- Gastroenterology, Digestive Endoscopy and Nutrition Unit, Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste, Italy
| | - Lissy de Ridder
- Department of Paediatric Gastroenterology, Erasmus Medical Center/Sophia Children's Hospital, Rotterdam, the Netherlands
| | - Ben Kang
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Christoph Norden
- Paediatric Department, Copenhagen University Hospital, Hvidovre, Denmark
| | - David C Wilson
- Department of Paediatric Gastroenterology and Nutrition, Royal Hospital for Children and Young People, Edinburgh, United Kingdom
| | | | - Dan Turner
- Juliet Keiden Institute of Pediatric Gastroenterology and Nutrition, Shaare Zedek Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Shlomi Cohen
- Pediatric Gastroenterology Institute, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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16
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Wetwittayakhlang P, Lakatos PL. Current Evidence for Combined Targeted Therapy for the Treatment of Inflammatory Bowel Disease. J Can Assoc Gastroenterol 2024; 7:22-29. [PMID: 38314172 PMCID: PMC10836999 DOI: 10.1093/jcag/gwad032] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2024] Open
Abstract
Biologicals and small molecules have revolutionized the medical management of inflammatory bowel diseases (IBD), yet they are only effective in a proportion of patients, and their impact on changing the natural history of the disease is still debatable. Recently, the concept of combining targeted biologics and small-molecule therapies has been introduced to the treatment of IBD. Dual-targeted therapy (sequential and combined), which is the combination of two targeted therapies, might be a reasonable choice for patients to break through the therapeutic ceiling. A recent randomized clinical trial (VEGA) provided the first controlled evidence that the short-term combination of two biological agents may lead to superior disease control than either of the agents alone in patients with ulcerative colitis (UC) without jeopardizing safety. Multiple studies are underway in both Crohn's disease and UC. Additionally, real-world evidence is accumulating in IBD patients receiving combination therapies with concomitant IBD and extraintestinal manifestations or in patients with medically refractory IBD. Of note, the majority of these patients were exposed to multiple biological agents earlier and lost response to at least one of the agents in the combination. This review summarizes current knowledge regarding this attractive novel therapeutic option in IBD. Clearly, more controlled data are needed to evaluate optimal timing, efficacy, and mitigation of safety concerns.
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Affiliation(s)
- Panu Wetwittayakhlang
- Division of Gastroenterology and Hepatology, McGill University Health Center, Montreal, Quebec, 1650 Cedar Ave, Montreal, QC, H3G 1A4, Canada
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, 15 Karnjanavanich Road, Hat Yai, Songkhla, 90110, Thailand
| | - Peter L Lakatos
- Division of Gastroenterology and Hepatology, McGill University Health Center, Montreal, Quebec, 1650 Cedar Ave, Montreal, QC, H3G 1A4, Canada
- Department of Oncology and Medicine, Semmelweis University, 1083, Korányi Sándor u. 2/a, Budapest H-1085, Hungary
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Ali Mohammed S, Elbaramawy A, Hassan Abd-Allah S, Elkholy A, Ibrahim Elsayed N, Hussein S. Therapeutic potentials of mesenchymal stem cells in the treatment of inflammatory bowel disease in rats. J Biochem Mol Toxicol 2024; 38:e23532. [PMID: 37676835 DOI: 10.1002/jbt.23532] [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: 06/19/2022] [Revised: 07/19/2023] [Accepted: 08/18/2023] [Indexed: 09/09/2023]
Abstract
Interleukin-1beta (IL-1β) and interleukin-17A (IL-17A) have strong pro-inflammatory activities that are involved in inflammatory bowel diseases (IBDs). Mesenchymal stem cell (MSC) therapy is considered a promising treatment for IBD. This study was performed to understand the role of rat Nlrp3 inflammasome, Hmgb1, and pro-inflammatory cytokines (IL-1β and IL-17a) in the pathogenesis of IBD. Also, to evaluate the role of human umbilical cord blood-MSCs (hUCB-MSCs) in the management of IBD. The rats were in four groups: normal controls, indomethacin-induced IBD group, indomethacin-induced IBD rats that received phosphate-buffered saline (PBS), and the IBD group that received hUCB-MSCs as a treatment. The messenger RNA (mRNA) expression levels of rat Nlrp3, Hmgb1, IL-1β, and IL-17a were evaluated by quantitative real-time polymerase chain reaction. Histopathological examination of the small intestinal tissues of the studied rats was performed. There was a significant upregulation of the rat Nlrp3, IL-1β, IL-17a mRNA expression (p < 0.001 for the three parameters), and Hmgb1 (p < 0.05) in the untreated IBD group compared to the normal control group. In the MSC-treated group, IL-1β, IL-17a, and rat Nlrp3 mRNA expression significantly decreased compared to both the untreated IBD group and PBS group (p < 0.05 for all). hUCB-MSCs ameliorated IBD in rats by downregulating the pro-inflammatory cytokines (IL-1β and IL-17a) and other inflammatory mediators such as Hmgb1 and rat Nlrp3.
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Affiliation(s)
- Shuzan Ali Mohammed
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Benha University, Benha, Egypt
| | - Azza Elbaramawy
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Benha University, Benha, Egypt
| | - Somia Hassan Abd-Allah
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Adel Elkholy
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Benha University, Benha, Egypt
| | - Nashwa Ibrahim Elsayed
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Benha University, Benha, Egypt
| | - Samia Hussein
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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Johnson AM, Loftus EV. Risankizumab to treat moderately to severely active Crohn's disease in adults: an evaluation of trials and data. Expert Rev Gastroenterol Hepatol 2023; 17:1169-1183. [PMID: 38095092 DOI: 10.1080/17474124.2023.2295496] [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: 05/18/2023] [Accepted: 12/12/2023] [Indexed: 12/20/2023]
Abstract
INTRODUCTION Risankizumab is a humanized monoclonal antibody that selectively inhibits interleukin (IL)-23. It is approved for the treatment of moderate-to-severe plaque psoriasis, psoriatic arthritis, and more recently moderate-to-severe Crohn's disease (CD). AREAS COVERED After examining the current landscape of CD management including therapies which are currently approved and those in late stages of development, we will review the interleukin pathway and discuss the specific mechanism of targeted IL-23 inhibition, summarize available clinical trial data on efficacy and safety of Risankizumab, consider future positioning of Risankizumab in the therapeutic armamentarium, and ultimately discuss future needs for the field. EXPERT OPINION Risankizumab represents the first and only targeted IL-23 inhibitor approved for the treatment of CD, providing a promising addition to the therapeutic armamentarium for CD, with a favorable safety profile and demonstrated efficacy in both biologic-naïve and exposed populations. It is possible that the targeted nature of Risankizumab may enhance efficacy and safety over combined IL-12/23 inhibition, with trials underway attempting to shed light on that hypothesis.
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Affiliation(s)
- Amanda M Johnson
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Edward V Loftus
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
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19
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Gallagher J, Rosh JR, Sahn B. The Future of Advanced Therapies for Pediatric Crohn's Disease. Paediatr Drugs 2023; 25:621-633. [PMID: 37612580 DOI: 10.1007/s40272-023-00590-x] [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] [Accepted: 08/07/2023] [Indexed: 08/25/2023]
Abstract
Pediatric Crohn's disease commonly presents with moderate-to-severe intestinal inflammation with a greater risk of complications if remission is not achieved. Anti-tumor necrosis factor therapies have offered the possibility of deep and durable remission; however, many children do not respond or no longer respond over time. Further, some children do not require broader systemic immunosuppression to achieve remission and are better served by an alternative treatment strategy. Proper utilization of advanced biologic and small-molecule therapies, which have become available for adult patients since anti-tumor necrosis factor medications, is paramount for tighter disease control for a large proportion of children. Newer advanced therapies such as anti-integrin and anti-interleukin biologics, and several small-molecule agents capitalize on various mechanisms through narrower immunologic targets and reduced immunogenicity. Given limited regulatory approvals of these agents for use in children with Crohn's disease, clinicians continue to rely on data extrapolated from clinical trials in adult patients, sparse pediatric studies, and a growing real-world experience for treatment selection and optimization. In this article, we discuss currently available treatment options, pipeline drugs, and relevant data as they pertain to some of the most pressing clinical challenges faced in treating pediatric Crohn's disease.
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Affiliation(s)
- Julie Gallagher
- Division of Pediatric Gastroenterology, Liver Diseases, and Nutrition, Steven and Alexandra Cohen Children's Medical Center, Northwell Health, 1991 Marcus Ave, Suite M100, New Hyde Park, NY, 11042, USA
| | - Joel R Rosh
- Division of Pediatric Gastroenterology, Liver Diseases, and Nutrition, Steven and Alexandra Cohen Children's Medical Center, Northwell Health, 1991 Marcus Ave, Suite M100, New Hyde Park, NY, 11042, USA
| | - Benjamin Sahn
- Division of Pediatric Gastroenterology, Liver Diseases, and Nutrition, Steven and Alexandra Cohen Children's Medical Center, Northwell Health, 1991 Marcus Ave, Suite M100, New Hyde Park, NY, 11042, USA.
- Feinstein Institutes for Medical Research, Manhasset, NY, USA.
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20
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Sahn B, Pascuma K, Kohn N, Tracey KJ, Markowitz JF. Transcutaneous auricular vagus nerve stimulation attenuates inflammatory bowel disease in children: a proof-of-concept clinical trial. Bioelectron Med 2023; 9:23. [PMID: 37849000 PMCID: PMC10583463 DOI: 10.1186/s42234-023-00124-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 09/11/2023] [Indexed: 10/19/2023] Open
Abstract
BACKGROUND Vagus nerve stimulation is an investigational anti-inflammatory therapy targeting the nervous system to modulate immune activity. This study evaluated the efficacy and safety of transcutaneous auricular VNS (ta-VNS) in patients with pediatric-onset Crohn's disease (CD) or ulcerative colitis (UC). METHODS Participants were 10-21 years of age with mild/moderate CD or UC and fecal calprotectin (FC) > 200 ug/g within 4 weeks of study entry. Subjects were randomized to receive either ta-VNS targeting the cymba conchae of the external left ear, or sham stimulation, of 5 min duration once daily for a 2-week period, followed by a cross over to the alternative stimulation for an additional 2 weeks. At week 4, all subjects received ta-VNS of 5 min duration twice daily until week 16. Primary study endpoints were clinical remission, and a ≥ 50% reduction in FC level from baseline to week 16. Heart rate variability measurements and patient-reported outcome questionnaires were completed during interval and week 16 assessments. RESULTS Twenty-two subjects were enrolled and analyzed (10 CD, 12 UC). Six of 10 with CD had a wPCDAI > 12.5 and 6/12 with UC had a PUCAI > 10 at baseline, correlating to mild to moderate symptom activity. Among the 12 subjects with active symptomatic disease indices at baseline, clinical remission was achieved in 3/6 (50%) with CD and 2/6 (33%) with UC at week 16. Despite all subjects having FC levels ≥ 200 within 4 weeks of enrollment, five subjects (4 UC, 1 CD) had FC levels < 200 at the baseline visit and were excluded from the FC analysis. Of the remaining 17, median baseline FC was 907 µg/g (IQR 411-2,120). At week 16, 11/17 (64.7%) of those with baseline FC ≥ 200 had a ≥ 50% reduction in FC (95% CI 38.3-85.8). In the UC subjects, there was an 81% median reduction in FC vs baseline (833 µg/g; p = 0.03) while in the CD subjects, median reduction in FC at 16 weeks was 51% (357 µg/g; p = 0.09). There were no safety concerns. CONCLUSION Noninvasive ta-VNS attenuated signs and symptoms in a pediatric cohort with mild to moderate inflammatory bowel disease. TRIAL REGISTRATION NCT03863704-Date of registration 3/4/2019.
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Affiliation(s)
- Benjamin Sahn
- Division of Pediatric Gastroenterology, Liver Diseases, & Nutrition, Steven & Alexandra Cohen Children's Medical Center, Northwell Health, 1991 Marcus Ave, Suite M100, New Hyde Park, NY, 11042, USA.
- Feinstein Institutes for Medical Research, Manhasset, NY, USA.
| | - Kristine Pascuma
- Division of Pediatric Gastroenterology, Liver Diseases, & Nutrition, Steven & Alexandra Cohen Children's Medical Center, Northwell Health, 1991 Marcus Ave, Suite M100, New Hyde Park, NY, 11042, USA
| | - Nina Kohn
- Feinstein Institutes for Medical Research, Manhasset, NY, USA
- Biostatistics Unit, Office of Academic Affairs, New Hyde Park, NY, USA
| | - Kevin J Tracey
- Feinstein Institutes for Medical Research, Manhasset, NY, USA
| | - James F Markowitz
- Division of Pediatric Gastroenterology, Liver Diseases, & Nutrition, Steven & Alexandra Cohen Children's Medical Center, Northwell Health, 1991 Marcus Ave, Suite M100, New Hyde Park, NY, 11042, USA
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21
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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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22
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Zhang X, Cui K, Wang X, Tong Y, Liu C, Zhu Y, You Q, Jiang Z, Guo X. Novel Hydrogen Sulfide Hybrid Derivatives of Keap1-Nrf2 Protein-Protein Interaction Inhibitor Alleviate Inflammation and Oxidative Stress in Acute Experimental Colitis. Antioxidants (Basel) 2023; 12:antiox12051062. [PMID: 37237928 DOI: 10.3390/antiox12051062] [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: 02/19/2023] [Revised: 04/26/2023] [Accepted: 05/02/2023] [Indexed: 05/28/2023] Open
Abstract
Ulcerative colitis (UC) is an idiopathic inflammatory disease of unknown etiology possibly associated with intestinal inflammation and oxidative stress. Molecular hybridization by combining two drug fragments to achieve a common pharmacological goal represents a novel strategy. The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway provides an effective defense mechanism for UC therapy, and hydrogen sulfide (H2S) shows similar and relevant biological functions as well. In this work, a series of hybrid derivatives were synthesized by connecting an inhibitor of Keap1-Nrf2 protein-protein interaction with two well-established H2S-donor moieties, respectively, via an ester linker, to find a drug candidate more effective for the UC treatment. Subsequently, the cytoprotective effects of hybrids derivatives were investigated, and DDO-1901 was identified as a candidate showing the best efficacy and used for further investigation on therapeutic effect on dextran sulfate sodium (DSS)-induced colitis in vitro and in vivo. Experimental results indicated that DDO-1901 could effectively alleviate DSS-induced colitis by improving the defense against oxidative stress and reducing inflammation, more potent than parent drugs. Compared with either drug alone, such molecular hybridization may offer an attractive strategy for the treatment of multifactorial inflammatory disease.
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Affiliation(s)
- Xian Zhang
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Keni Cui
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Xiaolu Wang
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
| | - Yuanyuan Tong
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Chihong Liu
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Yuechao Zhu
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Qidong You
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Zhengyu Jiang
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Xiaoke Guo
- State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
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23
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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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24
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Feagan BG, Sands BE, Sandborn WJ, Germinaro M, Vetter M, Shao J, Sheng S, Johanns J, Panés J. Guselkumab plus golimumab combination therapy versus guselkumab or golimumab monotherapy in patients with ulcerative colitis (VEGA): a randomised, double-blind, controlled, phase 2, proof-of-concept trial. Lancet Gastroenterol Hepatol 2023; 8:307-320. [PMID: 36738762 DOI: 10.1016/s2468-1253(22)00427-7] [Citation(s) in RCA: 109] [Impact Index Per Article: 54.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/30/2022] [Accepted: 12/01/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND Despite the introduction of new monoclonal antibodies and oral therapies for the treatment of ulcerative colitis, clinical remission rates remain low, underscoring the need for innovative treatment approaches. We assessed whether guselkumab plus golimumab combination therapy was more effective for ulcerative colitis than either monotherapy. METHODS We did a randomised, double-blind, controlled, proof-of-concept trial at 54 hospitals, academic medical centres, or private practices in nine countries. Eligible adults (aged ≥18 to 65 years) had a confirmed diagnosis of ulcerative colitis at least 3 months before screening and moderately-to-severely active ulcerative colitis (Mayo score 6-12) with a centrally-read baseline endoscopy subscore of 2 or higher. Patients were randomly assigned (1:1:1) using a computer-generated randomisation schedule to combination therapy (subcutaneous golimumab 200 mg at week 0, subcutaneous golimumab 100 mg at weeks 2, 6, and 10, and intravenous guselkumab 200 mg at weeks 0, 4, and 8, followed by subcutaneous guselkumab monotherapy 100 mg every 8 weeks for 32 weeks), golimumab monotherapy (subcutaneous golimumab 200 mg at week 0 followed by subcutaneous golimumab 100 mg at week 2 and every 4 weeks thereafter for 34 weeks), or guselkumab monotherapy (intravenous guselkumab 200 mg at weeks 0, 4, and 8, followed by subcutaneous guselkumab 100 mg every 8 weeks thereafter for 32 weeks). The primary endpoint was clinical response at week 12 (defined as a ≥30% decrease from baseline in the full Mayo score and a ≥3 points absolute reduction with either a decrease in rectal bleeding score of ≥1 point or a rectal bleeding score of 0 or 1). Efficacy was analysed in the modified intention-to-treat population up to week 38, which included all randomly assigned patients who received at least one (partial or complete) study intervention dose. Safety was analysed up to week 50, according to study intervention received among all patients who received at least one (partial or complete) dose of study intervention. This trial is complete and is registered with ClinicalTrials.gov, NCT03662542. FINDINGS Between Nov 20, 2018, and Nov 15, 2021, 358 patients were screened for eligibility, of whom 214 patients were randomly assigned to combination therapy (n=71), golimumab monotherapy (n=72), or guselkumab monotherapy (n=71). Of the 214 patients included, 98 (46%) were women and 116 (54%) were men and the mean age was 38·4 years (SD 12·0). At week 12, 59 (83%) of 71 patients in the combination therapy group had achieved clinical response compared with 44 (61%) of 72 patients in the golimumab monotherapy group (adjusted treatment difference 22·1% [80% CI 12·9 to 31·3]; nominal p=0·0032) and 53 (75%) of 71 patients in the guselkumab monotherapy group (adjusted treatment difference 8·5% [-0·2 to 17·1; nominal p=0·2155). At week 50, 45 (63%) of 71 patients in the combination therapy group, 55 (76%) of 72 patients in the golimumab monotherapy group, and 46 (65%) of 71 patients in the guselkumab monotherapy group had reported at least one adverse event. The most common adverse events were ulcerative colitis, upper respiratory tract infection, headache, anaemia, nasopharyngitis, neutropenia, and pyrexia. No deaths, malignancies, or cases of tuberculosis were reported during the combination induction period. One case of tuberculosis was reported in the combination therapy group and one case of colon adenocarcinoma was reported in the guselkumab monotherapy group; both occurred after week 12. Two deaths were reported after the final dose of study intervention (poisoning in the combination therapy group and COVID-19 in the guselkumab monotherapy group). INTERPRETATION Data from this proof-of-concept study suggest that combination therapy with guselkumab and golimumab might be more effective for ulcerative colitis than therapy with either drug alone. These findings require confirmation in larger trials. FUNDING Janssen Research and Development.
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Affiliation(s)
| | - Bruce E Sands
- Dr Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | | | - Marion Vetter
- Janssen Research and Development, Spring House, PA, USA
| | - Jie Shao
- Janssen Research and Development, Spring House, PA, USA
| | - Shihong Sheng
- Janssen Research and Development, Spring House, PA, USA
| | - Jewel Johanns
- Janssen Research and Development, Spring House, PA, USA
| | - Julián Panés
- Department of Gastroenterology, Hospital Clinic of Barcelona, IDIBAPS, CIBEREHD, Barcelona, Spain
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25
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Cheah E, Huang JG. Precision medicine in inflammatory bowel disease: Individualizing the use of biologics and small molecule therapies. World J Gastroenterol 2023; 29:1539-1550. [PMID: 36970587 PMCID: PMC10037250 DOI: 10.3748/wjg.v29.i10.1539] [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: 09/29/2022] [Revised: 01/17/2023] [Accepted: 02/21/2023] [Indexed: 03/14/2023] Open
Abstract
The advent of biologics and small molecules in inflammatory bowel disease (IBD) has marked a significant turning point in the prognosis of IBD, decreasing the rates of corticosteroid dependence, hospitalizations and improving overall quality of life. The introduction of biosimilars has also increased affordability and enhanced access to these otherwise costly targeted therapies. Biologics do not yet represent a complete panacea: A subset of patients do not respond to first-line anti-tumor necrosis factor (TNF)-alpha agents or may subsequently demonstrate a secondary loss of response. Patients who fail to respond to anti-TNF agents typically have a poorer response rate to second-line biologics. It is uncertain which patient would benefit from a different sequencing of biologics or even a combination of biologic agents. The introduction of newer classes of biologics and small molecules may provide alternative therapeutic targets for patients with refractory disease. This review examines the therapeutic ceiling in current treatment strategies of IBD and the potential paradigm shifts in the future.
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Affiliation(s)
- Eric Cheah
- Department of Gastroenterology and Clinical Nutrition, The Royal Children's Hospital Melbourne, Parkville, VIC 3052, Australia
| | - James Guoxian Huang
- Department of Paediatrics, Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore 119228, Singapore
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
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26
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Cheah E, Huang JG. Precision medicine in inflammatory bowel disease: Individualizing the use of biologics and small molecule therapies. World J Gastroenterol 2023; 29:1395-1406. [DOI: 10.3748/wjg.v29.i10.1395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/10/2023] Open
Abstract
The advent of biologics and small molecules in inflammatory bowel disease (IBD) has marked a significant turning point in the prognosis of IBD, decreasing the rates of corticosteroid dependence, hospitalizations and improving overall quality of life. The introduction of biosimilars has also increased affordability and enhanced access to these otherwise costly targeted therapies. Biologics do not yet represent a complete panacea: A subset of patients do not respond to first-line anti-tumor necrosis factor (TNF)-alpha agents or may subsequently demonstrate a secondary loss of response. Patients who fail to respond to anti-TNF agents typically have a poorer response rate to second-line biologics. It is uncertain which patient would benefit from a different sequencing of biologics or even a combination of biologic agents. The introduction of newer classes of biologics and small molecules may provide alternative therapeutic targets for patients with refractory disease. This review examines the therapeutic ceiling in current treatment strategies of IBD and the potential paradigm shifts in the future.
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Affiliation(s)
- Eric Cheah
- Department of Gastroenterology and Clinical Nutrition, The Royal Children's Hospital Melbourne, Parkville, VIC 3052, Australia
| | - James Guoxian Huang
- Department of Paediatrics, Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore 119228, Singapore,Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
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27
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State M, Negreanu L. Defining the Failure of Medical Therapy for Inflammatory Bowel Disease in the Era of Advanced Therapies: A Systematic Review. Biomedicines 2023; 11:544. [PMID: 36831079 PMCID: PMC9953124 DOI: 10.3390/biomedicines11020544] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/10/2023] [Accepted: 02/10/2023] [Indexed: 02/16/2023] Open
Abstract
BACKGROUND The expansion of advanced therapies for inflammatory bowel disease created a lag between the development of these new therapies and their incorporation and use in daily practice. At present, no clear definitions for treatment optimization, treatment failure or criteria to abandon therapy are available. We aimed to centralize criteria for a nonresponse to all available molecules and to summarize guideline principles for treatment optimization. METHODS We conducted a systematic review of studies that reported criteria for the treatment response to all advanced therapies (infliximab, adalimumab, golimumab, ustekinumab, vedolizumab and tofacitinib) in patients with inflammatory bowel disease. RESULTS Across trials, criteria for a response of both patients with ulcerative colitis and Crohn's disease are heterogenous. Investigators use different definitions for clinical and endoscopic remission, and endoscopic response and outcomes are assessed at variable time points. Current society guidelines provide heterogenous recommendations on treatment optimization. Most available data on loss of response concern anti-TNF molecules, and newer therapies are not included in the guidelines. CONCLUSION The lack of clear definitions and formal recommendations provide the premise for empirical treatment strategies and premature abandonment of therapies.
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Affiliation(s)
- Monica State
- Department 5, Internal Medicine—Gastroenterology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Colentina Clinical Hospital, 020125 Bucharest, Romania
| | - Lucian Negreanu
- Department 5, Internal Medicine—Gastroenterology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Emergency University Hospital, 050098 Bucharest, Romania
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28
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Feng Z, Kang G, Wang J, Gao X, Wang X, Ye Y, Liu L, Zhao J, Liu X, Huang H, Cao X. Breaking through the therapeutic ceiling of inflammatory bowel disease: Dual-targeted therapies. Biomed Pharmacother 2023; 158:114174. [PMID: 36587559 DOI: 10.1016/j.biopha.2022.114174] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Revised: 12/27/2022] [Accepted: 12/28/2022] [Indexed: 01/01/2023] Open
Abstract
Emerging biologics and small-molecule drugs have changed the clinical status quo of inflammatory bowel disease (IBD). However, current treatments remain at a standstill in terms of response and remission in many cases. Accumulating evidence indicates that dual-targeted therapy (DTT) could be promising in overcoming the existing ceiling of IBD treatment. However, data on the efficacy and safety of DTT on Crohn's disease and ulcerative colitis are still limited or insufficient. Moreover, there is a lack of studies delineating the mechanisms of DTT. Given that various targeted drugs have different targets among the extensive redundant inflammatory networks, DTT could result in various outcomes. In this review, we have summarized the current data on the safety, effectiveness, and clinical development status of novel targeted drugs related to refractory IBD, and have explored the mechanism of action of therapy. We have categorized therapeutic agents into "Therapeutic Agents Targeting Cellular Signaling Pathways" and "Therapeutic Agents Targeting Leukocyte Trafficking" based on the different therapeutic targets, and also by classifying therapeutic agents targeting the cellular signaling pathways into "JAK-dependent" and "JAK-independent," and placed the existing drug combinations into 3 categories based on their mechanisms, namely, overlapping, synergistic, and complementary effects. Lastly, we have proposed the possible mechanisms of DTT to conceive a theoretical framework for clinical decision-making and further drug development and research from an IBD standpoint.
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Affiliation(s)
- Zelin Feng
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Guangbo Kang
- Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China; Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China; Institute of Shaoxing, Tianjin University, Zhejiang 312300, China
| | - Jiewen Wang
- Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China; Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China; Institute of Shaoxing, Tianjin University, Zhejiang 312300, China
| | - Xingjie Gao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Tianjin Medical University, Tianjin 300070, China
| | - Xiaoli Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Yulin Ye
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Limin Liu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Jingwen Zhao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Xinjuan Liu
- Department of Gastroenterology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100016, China
| | - He Huang
- Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China; Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China.
| | - Xiaocang Cao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China.
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Dai C, Huang YH, Jiang M. Combination therapy in inflammatory bowel disease: Current evidence and perspectives. Int Immunopharmacol 2023; 114:109545. [PMID: 36508920 DOI: 10.1016/j.intimp.2022.109545] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 11/22/2022] [Accepted: 12/01/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND OBJECTIVE Inflammatory Bowel Diseases (IBD) are chronic nonspecific intestinal inflammatory diseases with a relapsing-remitting course, including Ulcerative Colitis (UC) and Crohn's Disease (CD). Combination therapy has been proposed as a strategy to enhance treatment efficacy in IBD. The aim of this study is to summarize current evidence and perspectives on combination therapies in IBD. METHODS Electronic databases such as PubMed, Ovid Embase, Medline, and Cochrane CENTRAL were searched to identify relevant studies. RESULTS Current evidence supports that the combination of infliximab and thiopurines is more effective than monotherapy in inducing and maintaining remission in IBD. Data on the combination of other biological agents such as adalimumab, vedolizumab, ustekinumab, and immunosuppressors is lacking or showed conflicting results. Vedolizumab seems a potentially effective maintenance regimen after calcineurin inhibitors-based rescue therapy in acute severe ulcerative colitis (ASUC). Dual Targeted Therapy, which is the combination of two biological agents and/or small molecules, might be a reasonable choice in patients with concomitant IBD and extraintestinal manifestations, or in patients with medical-refractory IBD who lack valid alternatives. Some safety concerns such as adverse events (serious and opportunistic infections) and malignancies (lymphoma and nonmelanoma skin cancer) were raised in combination therapies. CONCLUSIONS Combination therapies seem to be effective in some IBD patients such as refractory IBD patients or patients with extraintestinal manifestations, but it might be associated with an increased risk of adverse events and malignancies.
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Affiliation(s)
- Cong Dai
- Department of Gastroenterology, First Hospital of China Medical University, Shenyang City, Liaoning Province, China.
| | - Yu-Hong Huang
- Department of Gastroenterology, First Hospital of China Medical University, Shenyang City, Liaoning Province, China
| | - Min Jiang
- Department of Gastroenterology, First Hospital of China Medical University, Shenyang City, Liaoning Province, China
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30
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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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31
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Balderramo D. Role of the combination of biologics and/or small molecules in the treatment of patients with inflammatory bowel disease. World J Gastroenterol 2022; 28:6743-6751. [PMID: 36620336 PMCID: PMC9813940 DOI: 10.3748/wjg.v28.i47.6743] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 10/26/2022] [Accepted: 11/27/2022] [Indexed: 12/19/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a group of chronic diseases that includes ulcerative colitis, Crohn's disease, and indeterminate colitis. Patients with IBD require prolonged treatment and high utilization of healthcare resources for proper management. The treatment of patients with IBD is focused on achieving therapeutic goals including clinical, biochemical, and endoscopic variables that result in improvement of the quality of life and prevention of disability. Advanced IBD treatment includes tumor necrosis factor inhibitors, integrin antagonist, antagonist of the p40 subunit of interleukin 12/23, and small molecule drugs. However, despite the multiple treatments available, about 40% of patients are refractory to therapy and present with persistent symptoms that have a great impact on their quality of life, with hospitalization and surgery being necessary in many cases. Dual therapy, a strategy sometimes applicable to refractory IBD patients, includes the combination of two biologics or a biologic in combination with a small molecule drug. There are two distinct scenarios in IBD patients in which this approach can be used: (1) Refractory active luminal disease without extraintestinal manifestations; and (2) patients with IBD in remission, but with active extraintestinal manifestations or immune-mediated inflammatory diseases. This review provides a summary of the results (clinical response and remission) of different combinations of advanced drugs in patients with IBD, both in adults and in the pediatric population. In addition, the safety profile of different combinations of dual therapy is analyzed. The use of newer combinations, including recently approved treatments, the application of new biomarkers and artificial intelligence, and clinical trials to establish effectiveness during long-term follow-up, are needed to establish new strategies for the use of advanced treatments in patients with refractory IBD.
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Affiliation(s)
- Domingo Balderramo
- Department of Gastroenterology, Hospital Privado Universitario de Córdoba, Instituto Universitario de Ciencias Biomédicas de Córdoba, Córdoba 5016, Argentina
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32
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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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33
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Garcia NM, Cohen NA, Rubin DT. Treat-to-target and sequencing therapies in Crohn's disease. United European Gastroenterol J 2022; 10:1121-1128. [PMID: 36507876 PMCID: PMC9752313 DOI: 10.1002/ueg2.12336] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 10/25/2022] [Indexed: 12/15/2022] Open
Abstract
Crohn's disease (CD) is a chronic immune-mediated inflammatory condition which can negatively impact a patient's quality of life. The traditional management strategy for CD has focused on symptomatic control, however, this approach fails to prevent organ damage and to change the progressive course of this disease. Thus, the field has moved towards a treat-to-target strategy that includes identifying individualized objective targets, choosing a therapy based on individual factors that include disease severity and risk, closely monitoring disease activity at predefined time points, and optimizing therapies as needed. Due to the increasing number of therapies approved for CD, this review explores the various factors which should be considered in the sequencing of treatment options together with using the treat-to-target framework to control disease activity early in its course and provide holistic patient care.
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Affiliation(s)
- Nicole M. Garcia
- University of Chicago Medicine Inflammatory Bowel Disease CenterChicagoIllinoisUSA
| | - Nathaniel A. Cohen
- University of Chicago Medicine Inflammatory Bowel Disease CenterChicagoIllinoisUSA
| | - David T. Rubin
- University of Chicago Medicine Inflammatory Bowel Disease CenterChicagoIllinoisUSA,University of Chicago MacLean Center for Clinical Medical EthicsChicagoIllinoisUSA
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34
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Danese S, Solitano V, Jairath V, Peyrin-Biroulet L. The future of drug development for inflammatory bowel disease: the need to ACT (advanced combination treatment). Gut 2022; 71:2380-2387. [PMID: 35701092 DOI: 10.1136/gutjnl-2022-327025] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Accepted: 06/02/2022] [Indexed: 12/23/2022]
Affiliation(s)
- Silvio Danese
- Gastroenterology and Gastrointestinal Endoscopy Unit, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milano, Italy
| | - Virginia Solitano
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Vipul Jairath
- Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada.,Alimentiv, London, Ontario, Canada
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35
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Berera S, Ioannou SC, Morillo D, Mantero AMA, Pignac-Kobinger J, Colina N, Santander AM, Fernandez I, Quintero MA, Rodriguez J, Kerman DH, Damas OM, Czul F, Sussman DA, Abreu MT, Deshpande AR. Combining Pentoxifylline With Vedolizumab for Crohn's Disease: Results of a Randomised, Placebo-controlled Pilot Study. J Crohns Colitis 2022; 16:1687-1695. [PMID: 35642747 DOI: 10.1093/ecco-jcc/jjac074] [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: 02/10/2022] [Revised: 04/05/2022] [Accepted: 05/30/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS The efficacy of current biologics may be limited by targeting only one pathway. Pentoxifylline [PTX] interferes with tumour necrosis factor [TNF] gene expression. We performed a randomised, placebo-controlled pilot study to determine if PTX plus vedolizumab [VDZ] in patients with Crohn's disease [CD] is safe and improves response compared with VDZ monotherapy. METHODS Thirty adult patients with active CD were randomised to VDZ/PTX or VDZ/placebo and followed for 24 weeks. Endoscopic activity and inflammatory cytokines were measured at baseline and Week 24. Descriptive statistics were used to determine estimates of effect. RESULTS Demographics were similar but baseline disease activity was higher in the VDZ/PTX group. There was no difference in clinical remission at Week 14 (60.0% vs 66.67%, odds ratio [OR] 0.76, 95% confidence interval [CI] 0.16, 3.51) or steroid-free clinical remission at Week 24 in patients receiving VDZ/PTX. Improved clinical response was noted in the VDZ/PTX group at Weeks 6, 14, and 24 [Week 6: 20% vs 6.67%, Week 14: 26.67% vs 6.67%, Week 24: 40% vs 20%]. The rate of endoscopic remission was similar between the groups [40% vs 33.33%], with a greater mean decrease in Simple Endoscopic Score-CD [SES-CD] and C-reactive protein [CRP] with VDZ/PTX [SES-CD -3.17 vs -0.15, CRP -5.56 vs 0.46]. An increase in serum TNF-α concentration was observed with VDZ/placebo group; PTX mitigated this effect. No serious adverse events occurred. CONCLUSIONS VDZ/PTX did not provide benefit over VDZ monotherapy in clinical or endoscopic remission but appeared to improve clinical response and was safe. These data should inform a fully powered study.
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Affiliation(s)
- Shivali Berera
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Stephanie C Ioannou
- Division of Digestive Health and Liver Diseases, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Diana Morillo
- Division of Digestive Health and Liver Diseases, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Alejandro M A Mantero
- Division of Biostatistics, Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Judith Pignac-Kobinger
- Division of Digestive Health and Liver Diseases, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Niurka Colina
- Division of Digestive Health and Liver Diseases, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Ana M Santander
- Division of Digestive Health and Liver Diseases, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Irina Fernandez
- Division of Digestive Health and Liver Diseases, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Maria Alejandra Quintero
- Division of Digestive Health and Liver Diseases, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Jennifer Rodriguez
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - David H Kerman
- Division of Digestive Health and Liver Diseases, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Oriana M Damas
- Division of Digestive Health and Liver Diseases, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Frank Czul
- Division of Gastroenterology, Mount Sinai Medical Center, Miami Beach, FL, USA
| | - Daniel A Sussman
- Division of Digestive Health and Liver Diseases, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Maria T Abreu
- Division of Digestive Health and Liver Diseases, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Amar R Deshpande
- Division of Digestive Health and Liver Diseases, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
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36
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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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37
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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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38
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Hudson AS, Almeida P, Huynh HQ. Dual Biologic Therapy in a Patient With Niemann-Pick Type C and Crohn Disease: A Case Report and Literature Review. JPGN REPORTS 2022; 3:e225. [PMID: 37168644 PMCID: PMC10158355 DOI: 10.1097/pg9.0000000000000225] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 05/18/2022] [Indexed: 05/13/2023]
Abstract
Dual biologic therapy has become a new area of interest in inflammatory bowel disease (IBD). Monogenic/polygenic IBD and the role of genetics in IBD is an evolving field, with many of these patients having difficult treatment courses. We present a case of a teenage patient with Niemann-Pick disease type C and Crohn colitis, who sustained clinical remission only after escalating to dual biologic therapy (anti-tumor necrosis factor alpha [infliximab] and anti-interleukin-12/anti-interleukin-23 [ustekinumab]). A literature review of dual biologic therapy in pediatric IBD revealed 8 case series and 1 cohort study. In pediatric patients with genetic disorders and IBD who are not responding adequately to biologic therapy, adding a second biologic medication with a different mechanism of action may be efficacious. Targeting both anti-tumor necrosis factor alpha (which induces pro-inflammatory cytokines) and the pro-inflammatory cytokines themselves (interleukin-12/interleukin-23) may be important in impaired macrophage function and increased cytokine response. Our case adds to the sparse literature on the utility of combining ustekinumab and infliximab in pediatric IBD and is the first to describe its use for treating ongoing active luminal disease.
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Affiliation(s)
- Alexandra S. Hudson
- From the Department of Pediatrics, Division of Pediatric Gastroenterology and Nutrition, University of Alberta, Edmonton, Alberta, Canada
| | - Patricia Almeida
- From the Department of Pediatrics, Division of Pediatric Gastroenterology and Nutrition, University of Alberta, Edmonton, Alberta, Canada
| | - Hien Q. Huynh
- From the Department of Pediatrics, Division of Pediatric Gastroenterology and Nutrition, University of Alberta, Edmonton, Alberta, Canada
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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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Abstract
PURPOSE OF REVIEW Nearly one-third of patients with inflammatory bowel disease (IBD) do not achieve remission despite our best therapies. When this happens, it is critical to understand the reason for treatment failure. Once nonresponse is confirmed, these patients should be referred to an IBD centre for multidisciplinary care. This review will discuss the remaining treatment options, including escalation of biologics to unlicensed doses, combination biologics, nonvalidated therapies and surgical options. It will additionally provide updates in the management of acute severe ulcerative colitis (ASUC). RECENT FINDINGS There is an increasing interest in combination biologics to treat refractory IBD, although data supporting its safety and effectiveness are limited. The use of hyperbaric oxygen, mesenchymal stem cell therapy and dietary interventions also show early promise in this area. Studies have additionally focused on personalized therapy to identify aggressive phenotypes and predict treatment response in these challenging patients. In ASUC, infliximab and cyclosporine remain mainstays of treatment, and tofacitinib shows promise as a salvage therapy. SUMMARY Refractory IBD is common, yet large knowledge gaps remain. Recent and ongoing studies have focused on medical, surgical and dietary approaches with mixed success. Larger prospective studies are desperately needed to address this complex issue.
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Tse CS, Dulai PS. Dual Advanced Therapies and Novel Pharmacotherapies for Moderately to Severely Active Crohn's Disease. Gastroenterol Clin North Am 2022; 51:283-298. [PMID: 35595415 DOI: 10.1016/j.gtc.2021.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Abstract
Over the past 2 decades, there have been incredible advances in the pharmacotherapeutic options for the treatment of patients with moderately to severely active Crohn's disease. Despite the leaps and strides in safety, efficacy, and mechanistic specificity of treatment targets, a significant portion (up to ∼20-50%) of patients have refractory Crohn's disease ± concomitant rheumatologic disease/extraintestinal manifestations for which existing biologic and small molecule therapies are ineffective. In this review, we will explore the available evidence for the use of dual advanced therapies (combination of biologic and/or small molecule therapies) and novel pharmacotherapies in phase 2 to 3 clinical trials.
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Affiliation(s)
- Chung Sang Tse
- Division of Gastroenterology, University of California, San Diego, 9500 Gilman Drive, MC 0956, La Jolla, CA 92093-0956, USA.
| | - Parambir S Dulai
- Division of Gastroenterology, University of California, San Diego, 9500 Gilman Drive, MC 0956, La Jolla, CA 92093-0956, USA
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42
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Xiao X, Mao X, Chen D, Yu B, He J, Yan H, Wang J. miRNAs Can Affect Intestinal Epithelial Barrier in Inflammatory Bowel Disease. Front Immunol 2022; 13:868229. [PMID: 35493445 PMCID: PMC9043318 DOI: 10.3389/fimmu.2022.868229] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 03/18/2022] [Indexed: 11/17/2022] Open
Abstract
The most obvious pathological characterization of inflammatory bowel disease (IBD) is intestinal epithelium erosion and severe inflammation invasion. Micro-ribonucleic acids (miRNA or microRNA), single-stranded noncoding RNAs of ~22 nucleotides, have been considered as the potential therapeutic targets in the pathogenesis of IBD. Many previous studies have focused on the mechanisms that miRNAs use to regulate inflammation, immunity, and microorganisms in IBD. The review highlights in detail the findings of miRNAs in the intestinal epithelial barrier of IBD, and focuses on their gene targets, signaling pathways associated with IBD, and some potential therapies. It will be beneficial for the elucidation of the interaction between miRNAs and the intestinal epithelial barrier in IBD and provide a theoretical reference for preventing and treating IBD in the future.
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Affiliation(s)
- Xiangjun Xiao
- Institute of Animal Nutrition, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Chengdu, China
| | - Xiangbing Mao
- Institute of Animal Nutrition, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Chengdu, China
| | - Daiwen Chen
- Institute of Animal Nutrition, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Chengdu, China
| | - Bing Yu
- Institute of Animal Nutrition, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Chengdu, China
| | - Jun He
- Institute of Animal Nutrition, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Chengdu, China
| | - Hui Yan
- Institute of Animal Nutrition, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Chengdu, China
| | - Jianping Wang
- Institute of Animal Nutrition, Sichuan Agricultural University, Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Key Laboratory of Animal Disease-Resistant Nutrition and Feed of China Ministry of Agriculture and Rural Affairs, Key Laboratory of Animal Disease-Resistant Nutrition of Sichuan Province, Chengdu, China
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Hanzel J, Hulshoff MS, Grootjans J, D'Haens G. Emerging therapies for ulcerative colitis. Expert Rev Clin Immunol 2022; 18:513-524. [PMID: 35477319 DOI: 10.1080/1744666x.2022.2069562] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
INTRODUCTION Despite advances in the medical management of ulcerative colitis (UC), a subgroup of patients does not respond to currently available therapies. A number of novel drugs are in late stages of clinical development or have recently received regulatory approval for UC. AREAS COVERED This review focuses on three drug classes that have recently been approved or are awaiting approval for UC: antibodies against interleukin (IL)-23, sphingosine-1-phosphate receptor (S1PR) modulators, and selective inhibitors of Janus kinases (JAK). We provide an overview of their mechanism of action and summarize available evidence for their efficacy and safety. Finally, we discuss expected future challenges in UC management. EXPERT OPINION The evaluated drugs have demonstrated efficacy with an acceptable safety profile. IL-23 antagonists appear to be safest with very few (serious) adverse events, while the use of S1PR modulators or JAK inhibitors has been associated with infectious and cardiovascular/thromboembolic events, albeit in low numbers. Although advances in drug development are promising, there is an urgent need for (validated) biomarkers to guide rational treatment selection. The scarcity of head-to-head trials also complicates comparisons between available drugs. Breaking the therapeutic ceiling of efficacy in UC will require marked advances in management extending well beyond drug development.
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Affiliation(s)
- Jurij Hanzel
- Faculty of Medicine, University of Ljubljana, Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Melanie S Hulshoff
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centres, Academic Medical Centre, Amsterdam, the Netherlands
| | - Joep Grootjans
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centres, Academic Medical Centre, Amsterdam, the Netherlands
| | - Geert D'Haens
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centres, Academic Medical Centre, Amsterdam, the Netherlands
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Dual Biologic Therapy for the Treatment of Pediatric Inflammatory Bowel Disease: A Review of the Literature. J Clin Med 2022; 11:jcm11072004. [PMID: 35407612 PMCID: PMC9000175 DOI: 10.3390/jcm11072004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 03/29/2022] [Accepted: 04/01/2022] [Indexed: 12/17/2022] Open
Abstract
Background: pediatric patients with inflammatory bowel diseases (IBD) who qualify for biological therapy represent a group of severely ill patients. They have never been successful with conventional medication. Biologic medications in monotherapy are frequently used in the disease course, however they result in a 1-year remission, which can be maintained in approximately 40% of IBD patients. Method: the present study aims to summarize the review of literature data on the use of therapy with a combination of two biological and small molecule drugs, anti-TNF (infliximab, adalimumab), vedolizumab and ustekinumab, as well as Janus kinase inhibitors (tofacitinib). The risks associated with the use of dual biological therapy and potential adverse effects are particularly important. The literature data was reviewed using the following terms: “use of combination biologic in paediatric IBD”, “combination biologics”, and “dual biologic for treatment of Inflammatory Bowel Disease”. Conclusion: the use of dual biological therapy is a new therapeutic option. In pediatric IBD, combining the different mechanisms of action of the two biological drugs seems to be safe and effective. Anti-TNF drugs with vedolizumab or ustekinumab may be a particularly beneficial combination. Nevertheless, the clarification and justification of potential advantages of combined biological therapies in further studies, such as randomized control trials, are needed.
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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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Au M, Mitrev N, Leong RW, Kariyawasam V. Dual biologic therapy with ocrelizumab for multiple sclerosis and vedolizumab for Crohn's disease: A case report and review of literature. World J Clin Cases 2022; 10:2569-2576. [PMID: 35434082 PMCID: PMC8968582 DOI: 10.12998/wjcc.v10.i8.2569] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 11/21/2021] [Accepted: 02/10/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Little is known about the safety and efficacy of using two or more biologics for the treatment of immune-mediated diseases, including Crohn's disease (CD). CASE SUMMARY This case report and narrative review demonstrate the potential safety of dual biologic therapy (DBT) in a 45-year-old female with two separate immune-mediated diseases. She had a history of multiple sclerosis for which she was receiving treatment with ocrelizumab, and she had been recently diagnosed with CD after presenting with diarrhoea. The CD diagnosis was confirmed radiologically, endoscopically, histologically, and biochemically. The patient received treatment with vedolizumab, a gut-specific inhibitor of the α4β7 integrin on leukocytes. No adverse reactions were observed for the duration of treatment. The safety of ocrelizumab and vedolizumab for the treatment of different immune-mediated diseases was demonstrated. CONCLUSION DBT may be a safe and effective option for the treatment of refractory disease or multiple immune-mediated diseases. Newer biologics, which have improved safety profiles and gut specificity, may provide promising avenues for treatment. However, caution must be exercised in the appropriate selection of biologics given their inherent immunosuppressive properties, side effects, and efficacy profiles. Current evidence suggests that biologic therapy is not associated with a worse prognosis in patients with coronavirus disease 2019, but treatment decisions should be made in a multidisciplinary setting. Further research from controlled trials is needed to better understand the safety profile of DBT in CD. The immunopathological mechanisms underlying DBT also remain to be clarified.
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Affiliation(s)
- Michael Au
- Department of Gastroenterology and Hepatology, Blacktown and Mt Druitt Hospitals, Western Sydney Local Health District, Sydney 2148, New South Wales, Australia
- Blacktown Clinical School, Western Sydney University, Blacktown 2148, New South Wales, Australia
| | - Nikola Mitrev
- Department of Gastroenterology and Hepatology, Blacktown Hospital, Western Sydney Local Health District, Blacktown 2148, New South Wales, Australia
| | - Rupert W Leong
- Endoscopy Department and Inflammatory Bowel Disease Service, Concord Hospital, Sydney 2137, New South Wales, Australia
- Concord Clinical School, University of Sydney, Sydney 2137, New South Wales, Australia
| | - Viraj Kariyawasam
- Blacktown Clinical School, Western Sydney University, Blacktown 2148, New South Wales, Australia
- Inflammatory Bowel Disease Service, Blacktown Hospital, Western Sydney Local Health District, Blacktown 2148, New South Wales, Austria
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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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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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Maintenance Therapy in Crohn's Disease: Does the Drug Matter? Clin Gastroenterol Hepatol 2022; 20:472-473. [PMID: 33839274 DOI: 10.1016/j.cgh.2021.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/01/2021] [Accepted: 04/03/2021] [Indexed: 02/07/2023]
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