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De Bernardi A, Bezzio C, Puricelli M, Gilardi D, Saibeni S. Combining Advanced Targeted Therapy in Inflammatory Bowel Disease: Current Practice and Future Directions. J Clin Med 2025; 14:590. [PMID: 39860594 PMCID: PMC11766407 DOI: 10.3390/jcm14020590] [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: 12/16/2024] [Revised: 01/07/2025] [Accepted: 01/16/2025] [Indexed: 01/27/2025] Open
Abstract
Background/Objectives: Despite the increasing number of available medications, a significant proportion of IBD patients fail to achieve the current therapeutic targets. Uncontrolled IBD has a significant impact on patients' quality of life and on overall costs for the healthcare system. Given the complex pathophysiology of IBD, Combined Advanced Targeted Therapy (CATT), involving the combination of biologics/small molecules, appears to have biological plausibility and is gaining increasing interest. The aim of this narrative review is to provide the current evidence regarding CATT in IBD and propose future developments in this field. Methods: Relevant literature evidence was searched with pertinent MeSH terms in the most important database. Results: Available evidence of CATT in IBD provides encouraging results in terms of efficacy and effectiveness, with an acceptable safety profile. CATT may represent a therapeutic solution for patients with "difficult-to-treat" IBD or with concomitant immune-mediated inflammatory diseases. However, current data are restricted by an overall low level of evidence and by the short follow-up. Conclusions: There are no data concluding the superiority of one combination therapy over another. Various therapeutic schemes could be applied in the near future. Further studies are needed to provide recommendations and integrate this therapeutic strategy into everyday clinical practice.
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Affiliation(s)
- Alice De Bernardi
- IBD Unit, Gastroenterology Unit, Rho Hospital, ASST Rhodense, 20017 Rho, Italy; (A.D.B.); (M.P.); (D.G.)
| | - Cristina Bezzio
- IBD Centre, IRCCS Humanitas, Research Hospital, 20089 Rozzano, Italy;
- Department of Biomedical Sciences, Humanitas University, 20072 Milan, Italy
| | - Michele Puricelli
- IBD Unit, Gastroenterology Unit, Rho Hospital, ASST Rhodense, 20017 Rho, Italy; (A.D.B.); (M.P.); (D.G.)
| | - Daniela Gilardi
- IBD Unit, Gastroenterology Unit, Rho Hospital, ASST Rhodense, 20017 Rho, Italy; (A.D.B.); (M.P.); (D.G.)
| | - Simone Saibeni
- IBD Unit, Gastroenterology Unit, Rho Hospital, ASST Rhodense, 20017 Rho, Italy; (A.D.B.); (M.P.); (D.G.)
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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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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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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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Kelly-Goss MR, Badran YR, Dougan M. Update on Immune Checkpoint Inhibitor Enterocolitis. Curr Gastroenterol Rep 2022; 24:171-181. [PMID: 36264425 PMCID: PMC9583048 DOI: 10.1007/s11894-022-00852-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/29/2022] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW Immune checkpoint inhibitor (ICI) therapy revolutionized the treatment of multiple solid and hematologic malignancies. Yet, with it came profound inflammatory toxicities that mimic autoimmune diseases, termed immune-related adverse events (irAEs). Prominent among these is gastrointestinal inflammation, including a spectrum of gastritis, enteritis, and colitis. Here we synthesize an approach to immune checkpoint related enterocolitis (irEC) - including diagnostics and therapeutics - underpinned by new insights into the mechanism behind these phenomena. RECENT FINDINGS This review presents updated insights on how to approach irEC, including novel approaches to selective immunosuppressive therapy, the role of fecal microbiota transplant, and the underlying cellular mechanisms of irEC. This review provides an update on irEC diagnosis and therapy, with considerations of new therapies and special patient populations. The field of gastrointestinal irAEs requires additional investigation, which will ultimately provide the tools required for patients to continue to receive life-saving ICI therapy.
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Affiliation(s)
- Molly R. Kelly-Goss
- Department of Medicine, Massachusetts General Hospital, Boston, MA 02114 USA
- Harvard Medical School, Boston, MA 02115 USA
| | - Yousef R. Badran
- Department of Medicine, Massachusetts General Hospital, Boston, MA 02114 USA
- Harvard Medical School, Boston, MA 02115 USA
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114 USA
| | - Michael Dougan
- Harvard Medical School, Boston, MA 02115 USA
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114 USA
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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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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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10
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Yu N, Sarwal D, Ash R, Aslinia FM. Triple therapy with adalimumab, ustekinumab and methotrexate for induction of remission in moderate to severe ileocolonic Crohn's disease with upper gastrointestinal involvement in a biologic-experienced individual. BMJ Case Rep 2021; 14:e243500. [PMID: 34645625 PMCID: PMC8515434 DOI: 10.1136/bcr-2021-243500] [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] [Accepted: 09/23/2021] [Indexed: 11/04/2022] Open
Abstract
Induction of remission in biologic-experienced individuals with moderate to severe Crohn's disease (CD) can be a challenge. We hereby present a case of CD with secondary non-response to infliximab. Adding methotrexate and switching to ustekinumab plus methotrexate did not stop the inflammatory process. Therefore, combination therapy with two classes of biologics consisting of ustekinumab and adalimumab plus methotrexate was initiated. He achieved clinical remission in 4 weeks and remained on triple therapy for 6 months which was subsequently tailored to adalimumab/methotrexate combination therapy due to insurance restriction on ustekinumab. He remained in remission for the duration of follow-up, 14 months after initiation of triple therapy and 8 months after switching to methotrexate/adalimumab biologic monotherapy. Triple therapy with anti-TNF, IL-12/23 inhibitor and methotrexate could potentially be an option for induction of remission in biologic-experienced individuals with good initial clinical response to anti-TNF agents.
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Affiliation(s)
- Na Yu
- Department of Medicine, Division of Gastroenterology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Dhruv Sarwal
- Department of Medicine, Division of Gastroenterology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Ryan Ash
- Department of Medicine, Division of Gastroenterology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Florence M Aslinia
- Department of Medicine, Division of Gastroenterology, University of Kansas Medical Center, Kansas City, Kansas, USA
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Tumor Necrosis Factor's Pathway in Crohn's Disease: Potential for Intervention. Int J Mol Sci 2021; 22:ijms221910273. [PMID: 34638616 PMCID: PMC8508644 DOI: 10.3390/ijms221910273] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/18/2021] [Accepted: 09/21/2021] [Indexed: 12/12/2022] Open
Abstract
Crohn’s disease (CD) is a chronic disorder characterized by full thickness patchy inflammation of the gastrointestinal tract. The pathogenesis is multifactorial and involves defective innate immune responses, microbiome alterations, and dysregulated activation of the acquired component of mucosal immunity. One of the molecular mediators that is involved at different levels in the initiation and progression of intestinal inflammation characteristic of CD is tumor necrosis factor (TNF). The present manuscript provides a comprehensive review focused on the potential role of TNF in the different phases of CD pathogenesis, particularly in light of its potential clinical implications. Currently available drugs blocking TNF are evaluated and discussed, specifically for open issues that still remain utilizing such therapy. TNF exerts a paramount role in the established phase of intestinal inflammation that characterizes CD patients, and anti-TNF biologics have definitely changed patient management, offering effective and safe options of treatment. Nonetheless, many patients still do not respond to anti-TNF therapy or experience unwanted side-effects. This could partially be due to the role that TNF plays in intestinal homeostasis that is particularly important during the early phase of the inflammatory process. In fact, emerging evidence supporting the dichotomous role of TNF and the identification of molecular markers will guide a more tailored and refined therapy for CD patients in the near future.
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12
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Abstract
The burden of inflammatory bowel disease (IBD) is increasing globally and imposes a high morbidity in patients with IBD. Advances have been made in medical management of IBD with the advent of novel therapies such as the biologics and small molecule drugs (SMDs). However, response to these medications is limited; with only 40% of patients achieving clinical remission at 1 year with a biologic. Hence, medical management of IBD is a rapidly evolving paradigm in which not only are new medications being developed but understanding how, when and in whom to use them is evolving. Dual targeted therapy (DTT), which is the combination of biologics and/or SMDs is an attractive concept as it is theoretically a potent and multidimensional anti-inflammatory treatment strategy. In this review, we present the published literature on the use of DTT and highlight its utility in clinical practice. The majority of studies on DTT are case reports and case series on the combination of dual biologic therapy. From the limited evidence available in patients with IBD, dual biologic therapy may be a safe option for patients with refractory IBD who have failed multiple biologic therapies and to manage extraintestinal manifestation of IBD. There are a handful of reports of combination therapy with a biologic and a SMD in patients with IBD. Further studies and randomized control trials are required to comprehensivretain hereely evaluate the safety and efficacy of DTT in IBD.
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Affiliation(s)
- Mahnur Haider
- Section of Internal Medicine and Geriatrics, Tulane University, New Orleans, LA
| | - Bret Lashner
- Department of Gastroenterology and Hepatology, Cleveland Clinic, OH
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13
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Kwapisz L, Raffals LE, Bruining DH, Pardi DS, Tremaine WJ, Kane SV, Papadakis KA, Coelho-Prabhu N, Kisiel JB, Heron V, Faubion WA, Loftus EV. Combination Biologic Therapy in Inflammatory Bowel Disease: Experience From a Tertiary Care Center. Clin Gastroenterol Hepatol 2021; 19:616-617. [PMID: 32068149 DOI: 10.1016/j.cgh.2020.02.017] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 01/29/2020] [Accepted: 02/03/2020] [Indexed: 02/07/2023]
Abstract
The global incidence of inflammatory bowel disease (IBD) has increased considerably during the past few decades.1 IBDs, composed of Crohn's disease (CD) and ulcerative colitis (UC), are characterized by heterogeneous presentation and widely variable clinical course. The therapeutic goals are to induce and maintain remission. Despite the current treatments available, many patients do not achieve this goal.
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Affiliation(s)
- Lukasz Kwapisz
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Laura E Raffals
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
| | - David H Bruining
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Darrell S Pardi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - William J Tremaine
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Sunanda V Kane
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | | | | | - John B Kisiel
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Valerie Heron
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - William A Faubion
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Edward V Loftus
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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14
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Abstract
Ulcerative colitis (UC) is a relapsing and remitting inflammatory disease of the colon with a variable course. Despite advances in treatment, only approximately 40% of patients achieve clinical remission at the end of a year, prompting the exploration of new treatment modalities. This review explores novel therapeutic approaches to UC, including promising drugs in various stages of development, efforts to maximize the efficacy of currently available treatment options, and non-medication-based modalities. Treatment approaches which show promise in impacting the future of UC management are highlighted.
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Affiliation(s)
- Robert P Hirten
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; ,
| | - Bruce E Sands
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; ,
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15
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Olbjørn C, Rove JB, Jahnsen J. Combination of Biological Agents in Moderate to Severe Pediatric Inflammatory Bowel Disease: A Case Series and Review of the Literature. Paediatr Drugs 2020; 22:409-416. [PMID: 32378002 PMCID: PMC7383034 DOI: 10.1007/s40272-020-00396-1] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Treatment with biological agents such as anti-tumor necrosis factors (TNFs) has become standard of care in moderate to severe pediatric inflammatory bowel disease (IBD). However, a significant proportion of patients experience loss of response to anti-TNFs, need treatment escalation, or develop side effects. There is no data in the literature regarding combination of biological agents in pediatric IBD. METHODS At our hospital, which is a tertiary referral center, we have combined the anti-TNF infliximab with either vedolizumab or ustekinumab in patients with severe pediatric IBD. The indications for dual biological therapy were insufficient efficacy of infliximab or vedolizumab monotherapy, or side effects such as psoriasis due to anti-TNFs. RESULTS Eight patients (four boys) aged 14-17.5 years received a combination of infliximab and vedolizumab due to only a partial response to infliximab, four with Crohn's disease (CD) and four with ulcerative colitis (UC). Clinical remission was achieved in four patients (3 UC) and four had a colectomy (3 CD, 1 UC). Five CD patients (3 girls) aged 11-17 years, on maintenance therapy with infliximab, developed psoriasis resistant to topical treatment. A combination of infliximab and ustekinumab resulted in clinical remission of CD without skin symptoms. No serious adverse events occurred in any of the patients on combination therapy. Thirteen publications report on combining biologicals, all in adult IBD. CONCLUSION In pediatric IBD, combining biological agents seems to be safe and beneficial in selected patients. The safety should be addressed in long-term follow-up studies.
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Affiliation(s)
- Christine Olbjørn
- Department of Pediatric and Adolescent Medicine, Akershus University Hospital, 1478, Lørenskog, Norway.
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
| | - Jon Bergreen Rove
- Department of Pediatric and Adolescent Medicine, Akershus University Hospital, 1478, Lørenskog, Norway
| | - Jørgen Jahnsen
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway
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16
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Romano C, Esposito S, Ferrara R, Cuomo G. Choosing the most appropriate biologic therapy for Crohn’s disease according to concomitant extra-intestinal manifestations, comorbidities, or physiologic conditions. Expert Opin Biol Ther 2019; 20:49-62. [PMID: 31690126 DOI: 10.1080/14712598.2020.1689953] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Ciro Romano
- Division of Internal Medicine, Department of Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Sergio Esposito
- Division of Internal Medicine, Department of Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Roberta Ferrara
- Division of Internal Medicine, Department of Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Giovanna Cuomo
- Division of Internal Medicine, Department of Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
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17
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A Rare Case of New-Onset Ulcerative Colitis following Initiation of Secukinumab. Case Rep Med 2019; 2019:2975631. [PMID: 31467555 PMCID: PMC6701396 DOI: 10.1155/2019/2975631] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 07/02/2019] [Accepted: 07/16/2019] [Indexed: 12/14/2022] Open
Abstract
Secukinumab is an IgG monoclonal antibody widely used for treatment of ankylosing spondylitis, psoriasis, and psoriatic arthritis. Recently, there has been increasing controversy regarding potential adverse effects of the drug especially in those with underlying inflammatory bowel disease. We present the case of a young male patient who developed severe new-onset ulcerative colitis following initiation of secukinumab for psoriasis, with excellent response and rapid resolution of symptoms with infliximab.
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18
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Pagnini C, Pizarro TT, Cominelli F. Novel Pharmacological Therapy in Inflammatory Bowel Diseases: Beyond Anti-Tumor Necrosis Factor. Front Pharmacol 2019; 10:671. [PMID: 31316377 PMCID: PMC6611384 DOI: 10.3389/fphar.2019.00671] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Accepted: 05/23/2019] [Indexed: 12/19/2022] Open
Abstract
Inflammatory bowel diseases (IBDs) are chronic conditions of the gastrointestinal tract in which dysregulated immune responses cause persistent inflammation of the gut mucosa. Biologic therapy with anti-TNF blockers has revolutionized the therapeutic management of IBD for their remarkable efficacy and potential impact on disease course and for many years has represented the sole treatment option for patients refractory or intolerant to conventional therapy. In recent years, more molecules, both biologically and chemically synthetized, have been developed as potential therapeutic options for IBD that target different molecular pathways aside from TNF blockade, and which have been proposed as targets for novel drugs. This is particularly relevant for the present, as well as future, management of IBD, considering that some patients are refractory to anti-TNF. This review will summarize the pharmacological options, either currently available or in the pipeline, for market approval to treat IBD, besides anti-TNF strategies, based on their mechanism(s) of action. We will also analyze the current evidence for effectiveness and safety, as well as offer perspective, regarding the potential implementation for such therapies in the future.
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Affiliation(s)
- Cristiano Pagnini
- Department of Gastroenterology and Digestive Endoscopy, S. Giovanni Addolorata Hospital, Rome, Italy
| | - Theresa T Pizarro
- Department of Medicine and Pathology, Case Western Reserve University, Digestive Health Institute, University Hospitals of Cleveland, Cleveland, OH, United States
| | - Fabio Cominelli
- Department of Medicine and Pathology, Case Western Reserve University, Digestive Health Institute, University Hospitals of Cleveland, Cleveland, OH, United States
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19
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Hedin CRH, Vavricka SR, Stagg AJ, Schoepfer A, Raine T, Puig L, Pleyer U, Navarini A, van der Meulen-de Jong AE, Maul J, Katsanos K, Kagramanova A, Greuter T, González-Lama Y, van Gaalen F, Ellul P, Burisch J, Bettenworth D, Becker MD, Bamias G, Rieder F. The Pathogenesis of Extraintestinal Manifestations: Implications for IBD Research, Diagnosis, and Therapy. J Crohns Colitis 2019; 13:541-554. [PMID: 30445584 DOI: 10.1093/ecco-jcc/jjy191] [Citation(s) in RCA: 122] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
This article reports on the sixth scientific workshop of the European Crohn's and Colitis Organisation [ECCO] on the pathogenesis of extraintestinal manifestations [EIMs] in inflammatory bowel disease [IBD]. This paper has been drafted by 15 ECCO members and 6 external experts [in rheumatology, dermatology, ophthalmology, and immunology] from 10 European countries and the USA. Within the workshop, contributors formed subgroups to address specific areas. Following a comprehensive literature search, the supporting text was finalized under the leadership of the heads of the working groups before being integrated by the group consensus leaders.
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Affiliation(s)
- C R H Hedin
- Gastroenterology unit, Patient Area Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - S R Vavricka
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - A J Stagg
- Centre for Immunobiology, Bart's and The London Medical School, Queen Mary University of London, London, UK
| | - A Schoepfer
- Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
| | - T Raine
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Teaching Hospitals NHS Foundation Trust, Cambridge, UK
| | - L Puig
- Department of Dermatology, Hospital de la Santa Creu i Sant Pau. Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain
| | - U Pleyer
- University Eye Clinic, Uveitis Center, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - A Navarini
- Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
| | | | - J Maul
- Gastroenterologie am Bayerischen Platz, Berlin, Germany
- Department of Medicine (Gastroenterology, Infectious Diseases, Rheumatology), Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - K Katsanos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Ioannina School of Medical Sciences, Ioannina, Greece
| | - A Kagramanova
- IBD Department, The Loginov Moscow Clinical Scientific Centre, Moscow, Russia
| | - T Greuter
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
- Gastroenterology Research Unit, Mayo Clinic, Rochester, MN, USA
| | - Y González-Lama
- IBD Unit, Gastroenterology and Hepatology Department, Puerta de Hierro University Hospital, Majadahonda, Madrid, Spain
| | - F van Gaalen
- Department of Rheumatology, Leiden University Medical Center [LUMC], Leiden, Netherlands
| | - P Ellul
- Department of Medicine, Division of Gastroenterology, Mater Dei Hospital, Msida, Malta
| | - J Burisch
- Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, University of Copenhagen, Copenhagen, Denmark
- Abdominal Center K, Medical Section, Bispebjerg and Frederiksberg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - D Bettenworth
- Department of Medicine B, Gastroenterology and Hepatology, University Hospital Münster, Münster, Germany
| | - M D Becker
- Department of Ophthalmology, Triemli Hospital, Zurich, Switzerland & Department of Ophthalmology, University of Heidelberg, Heidelberg, Germany
| | - G Bamias
- National and Kapodistrian University of Athens, GI Unit, 3rd Academic Department of Internal Medicine, Sotiria Hospital, Athens, Greece
| | - F Rieder
- Department of Gastroenterology, Hepatology and Nutrition; Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
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20
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Liefferinckx C, Verstockt B, Gils A, Tops S, Van Moerkercke W, Vermeire S, Franchimont D. Impact of first-line infliximab on the pharmacokinetics of second-line vedolizumab in inflammatory bowel diseases. United European Gastroenterol J 2019; 7:750-758. [PMID: 31316779 DOI: 10.1177/2050640619841538] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 03/09/2019] [Indexed: 01/11/2023] Open
Abstract
Background Very little is known about the impact of the wash-out period on the pharmacokinetics of a second-line biologic. Objective The objective of this article is to explore the impact of two different wash-out periods on the pharmacokinetics of vedolizumab and infliximab. Methods Patients switching from infliximab to vedolizumab were retrospectively identified. The population was divided into two groups according to wash-out period: <6 weeks or >6 weeks. Vedolizumab and infliximab trough levels (TLs) were determined and correlated with clinical and biological outcomes. Results A total of 71 inflammatory bowel disease patients were included. At week 6, in patients previously treated with infliximab, median vedolizumab TLs were 21.9 µg/ml and 24.9 µg/ml for the <6 weeks and >6 weeks wash-out period, respectively (p = 0.31), whereas median residual infliximab TLs were 0.5 µg/ml and 0 µg/ml (p = 0.034). The rate of treatment discontinuation was similar (p = 0.64), and the infectious events were six and two for the <6 weeks and >6 weeks wash-out period, respectively (p = 0.12) by week 30. Conclusions This study suggests clinicians may not need to be concerned about the impact of wash-out period on the pharmacokinetics of the second-line biologic when switching infliximab to vedolizumab. More data are required on the impact of wash-out period on safety.
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Affiliation(s)
- Claire Liefferinckx
- Department of Gastroenterology, Hôpital Erasme, ULB, Brussels, Belgium.,Laboratoire de gastroenterology experimentale, ULB, Brussels, Belgium
| | - Bram Verstockt
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium.,KU Leuven, Department of Chronic Diseases, Metabolism and Ageing, Leuven, Belgium
| | - Ann Gils
- Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium
| | - Sophie Tops
- Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Belgium
| | - Wouter Van Moerkercke
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium.,Department of Gastroenterology, AZ Groeninge, Kortrijk, Belgium
| | - Severine Vermeire
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium.,KU Leuven, Department of Chronic Diseases, Metabolism and Ageing, Leuven, Belgium
| | - Denis Franchimont
- Department of Gastroenterology, Hôpital Erasme, ULB, Brussels, Belgium.,Laboratoire de gastroenterology experimentale, ULB, Brussels, Belgium
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21
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Combination Therapy With Vedolizumab and Tofacitinib in a Patient With Ulcerative Colitis and Spondyloarthropathy. Clin Gastroenterol Hepatol 2019; 17:794-796. [PMID: 30114486 DOI: 10.1016/j.cgh.2018.08.017] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 08/08/2018] [Indexed: 02/07/2023]
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22
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Richard N, Hazel EM, Haroon N, Inman RD. Simultaneous inhibition of α4/β7 integrin and tumour necrosis factor-α in concomitant spondyloarthritis and inflammatory bowel disease. Ann Rheum Dis 2018; 77:e86. [PMID: 29288208 DOI: 10.1136/annrheumdis-2017-212819] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 12/15/2017] [Indexed: 01/26/2023]
Affiliation(s)
- Nicolas Richard
- Division of Rheumatology, University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada
- McGill University Health Centre, Montreal General Hospital, Montreal, Quebec, Canada
| | - Elizabeth M Hazel
- McGill University Health Centre, Montreal General Hospital, Montreal, Quebec, Canada
| | - Nigil Haroon
- Division of Rheumatology, University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada
| | - Robert D Inman
- Division of Rheumatology, University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada
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23
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Mao EJ, Lewin S, Terdiman JP, Beck K. Safety of dual biological therapy in Crohn's disease: a case series of vedolizumab in combination with other biologics. BMJ Open Gastroenterol 2018; 5:e000243. [PMID: 30538822 PMCID: PMC6254738 DOI: 10.1136/bmjgast-2018-000243] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 10/03/2018] [Accepted: 10/16/2018] [Indexed: 12/18/2022] Open
Abstract
Uncertainty exists regarding safety and efficacy of dual biological therapy (DBT) in inflammatory bowel disease. We present four cases of DBT in Crohn’s disease. Three patients had refractory disease non-responsive to biological monotherapy or combination therapy with immunomodulators. One patient had concomitant ankylosing spondylitis. DBT was implemented by combining vedolizumab with an anti tumour necrosis antibody or with ustekinumab. DBT was well-tolerated, though two patients did experience self-limited infections. The efficacy of DBT remains unproven but it appears promising as three of the four patients achieved clinical remission. Our case series contributes insight into the safety of DBT that incorporates vedolizumab for future efficacy studies.
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Affiliation(s)
- Eric J Mao
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California, Davis, Sacramento, California, USA
| | - Sara Lewin
- Department of Medicine, Division of Gastroenterology, University of California, San Francisco, San Francisco, California, USA
| | - Jonathan P Terdiman
- Department of Medicine, Division of Gastroenterology, University of California, San Francisco, San Francisco, California, USA
| | - Kendall Beck
- Department of Medicine, Division of Gastroenterology, University of California, San Francisco, San Francisco, California, USA
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24
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Paramsothy S, Rosenstein AK, Mehandru S, Colombel JF. The current state of the art for biological therapies and new small molecules in inflammatory bowel disease. Mucosal Immunol 2018; 11:1558-1570. [PMID: 29907872 PMCID: PMC6279599 DOI: 10.1038/s41385-018-0050-3] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 05/15/2018] [Accepted: 05/21/2018] [Indexed: 02/06/2023]
Abstract
The emergence of biologic therapies is arguably the greatest therapeutic advance in the care of inflammatory bowel disease (IBD) to date, allowing directed treatments targeted at highly specific molecules shown to play critical roles in disease pathogenesis, with advantages in potency and selectivity. Furthermore, a large number of new biologic and small-molecule therapies in IBD targeting a variety of pathways are at various stages of development that should soon lead to a dramatic expansion in our therapeutic armamentarium. Additionally, since the initial introduction of biologics, there have been substantial advances in our understanding as to how biologics work, the practical realities of their administration, and how to enhance their efficacy and safety in the clinical setting. In this review, we will summarize the current state of the art for biological therapies in IBD, both in terms of agents available and their optimal use, as well as preview future advances in biologics and highly targeted small molecules in the IBD field.
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Affiliation(s)
- Sudarshan Paramsothy
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Adam K. Rosenstein
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA,PrIISM Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Saurabh Mehandru
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA,PrIISM Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jean-Frederic Colombel
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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25
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Felice C, Pugliese D, Papparella LG, Pizzolante F, Onori E, Gasbarrini A, Rapaccini GL, Guidi L, Armuzzi A. Clinical management of rheumatologic conditions co-occurring with inflammatory bowel diseases. Expert Rev Clin Immunol 2018; 14:751-759. [DOI: 10.1080/1744666x.2018.1513329] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Carla Felice
- IBD Unit, Presidio Columbus, Fondazione Policlinico A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Daniela Pugliese
- IBD Unit, Presidio Columbus, Fondazione Policlinico A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Luigi Giovanni Papparella
- IBD Unit, Presidio Columbus, Fondazione Policlinico A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Fabrizio Pizzolante
- IBD Unit, Presidio Columbus, Fondazione Policlinico A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Eugenia Onori
- Dipartimento di Medicina Interna, Università degli studi dell’Aquila, L’Aquila, Italy
| | - Antonio Gasbarrini
- Department of Internal Medicine, Gastroenterology Division, Fondazione Policlinico A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Gian Lodovico Rapaccini
- IBD Unit, Presidio Columbus, Fondazione Policlinico A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Luisa Guidi
- IBD Unit, Presidio Columbus, Fondazione Policlinico A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Alessandro Armuzzi
- IBD Unit, Presidio Columbus, Fondazione Policlinico A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
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26
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Hirten RP, Iacucci M, Shah S, Ghosh S, Colombel JF. Combining Biologics in Inflammatory Bowel Disease and Other Immune Mediated Inflammatory Disorders. Clin Gastroenterol Hepatol 2018; 16:1374-1384. [PMID: 29481970 DOI: 10.1016/j.cgh.2018.02.024] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 01/08/2018] [Accepted: 02/17/2018] [Indexed: 02/07/2023]
Abstract
Current therapies used in the treatment of inflammatory bowel disease (IBD) are not effective in all patients. Biologic agents result in approximately 40% remission rates at 1 year in selected populations, prompting a growing interest in combining biologic therapy to improve outcomes. There are limited published data regarding the efficacy and safety of combination targeted therapy in IBD specifically, which include only 1 exploratory randomized control trial and 3 case reports or series. This review evaluates the published literature regarding this therapeutic paradigm in IBD and its extensive utilization in the treatment of other immune-mediated inflammatory disorders. The combination of biologic therapies demonstrates variable degrees of efficacy and highlights some safety concerns, depending upon the agents used and the disease state treated. A trial (Clinical Trials.gov Identifier: NCT02764762) combining vedolizumab and adalimumab is currently underway evaluating the effectiveness and safety of this approach in patients with Crohn's disease, which should provide further insight into this treatment concept. While combination biologic therapy is an attractive strategy, the lack of consistent superior efficacy as well as safety concerns militates the need for further trials prior to its general application in IBD.
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Affiliation(s)
- Robert P Hirten
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York.
| | - Marietta Iacucci
- Institute of Immunology & Immunotherapy, NIHR Biomedical Research Centre IBD Theme, Institute of Translational Medicine, University of Birmingham, Birmingham, United Kingdom
| | - Shailja Shah
- Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Subrata Ghosh
- Institute of Immunology & Immunotherapy, NIHR Biomedical Research Centre IBD Theme, Institute of Translational Medicine, University of Birmingham, Birmingham, United Kingdom
| | - Jean-Frederic Colombel
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
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27
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Scribano ML. Vedolizumab for inflammatory bowel disease: From randomized controlled trials to real-life evidence. World J Gastroenterol 2018; 24:2457-2467. [PMID: 29930467 PMCID: PMC6010939 DOI: 10.3748/wjg.v24.i23.2457] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 05/06/2018] [Accepted: 05/18/2018] [Indexed: 02/06/2023] Open
Abstract
The biologic antitumor necrosis factor alpha (anti-TNFα) agents have revolutionised the treatment of inflammatory bowel disease (IBD). However, some patients experience primary nonresponse, loss of response, or intolerance. Therefore, introducing a newer class of therapy with a mechanism of action that acts on different inflammatory pathways involved in IBD pathogenesis is appealing. Vedolizumab is a fully humanised monoclonal antibody that selectively targets α4β7 integrin. Based on the results of the pivotal clinical GEMINI trials, vedolizumab was approved for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) and Crohn’s disease (CD) refractory or intolerant to either conventional therapy or TNFα inhibitors. This review describes the efficacy, safety, and tolerability of vedolizumab reported in both randomized, controlled, clinical trials and from real-world experience in patients with UC and CD in order to identify its place in treatment algorithms for IBD.
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28
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Should we use anti-tumor necrosis factor agents or vedolizumab as first-line biological therapy in ulcerative colitis? Best Pract Res Clin Gastroenterol 2018; 32-33:17-25. [PMID: 30060934 DOI: 10.1016/j.bpg.2018.05.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 03/17/2018] [Accepted: 05/03/2018] [Indexed: 01/31/2023]
Abstract
Randomized controlled trials with direct comparisons between the different available biological agents in ulcerative colitis are lacking. The comparative efficacy, safety and tolerability, patient profile, patient preference and costs should be taken into account when choosing an appropriate first-line biological. Tumor necrosis factor antagonists have a systemic mode of action, while vedolizumab is mainly gut-selective, and this influences the clinical profile of both treatment options. Tofacitinib will further expand the therapeutic armamentarium in ulcerative colitis. Results of ongoing head-to-head trials between biological agents are likely to change clinical practice in the near future. Biomarkers that predict response to different treatment options in an individual patient are warranted.
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29
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Buer LCT, Høivik ML, Warren DJ, Medhus AW, Moum BA. Combining Anti-TNF-α and Vedolizumab in the Treatment of Inflammatory Bowel Disease: A Case Series. Inflamm Bowel Dis 2018; 24:997-1004. [PMID: 29668901 DOI: 10.1093/ibd/izx110] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Anti-tumor necrosis factor α (anti-TNF-α) is important in the treatment of inflammatory bowel disease, but some patients experience only a partial response. In these patients, a combination of anti-TNF-α and vedolizumab (VDZ) may act as a bridge until the full VDZ effect occurs. At present, clinical data on combination treatment with anti-TNF-α and VDZ are not available. The aim of this case series was to evaluate the safety and clinical response of combination therapy with anti-TNF-α and VDZ in clinical practice. METHODS All patients started on combination treatment with anti-TNF-α and VDZ from November 2015 to July 2016 were prospectively followed for at least 12 months. RESULTS Six patients with ulcerative colitis and four patients with Crohn's disease received combination treatment. These patients were followed for a median of 1712-20 months. No more adverse events than expected with anti-TNF-α alone were observed during combination treatment. At the end of follow-up, all patients were in clinical remission, and 8 patients could discontinue anti-TNF-α treatment and receive VDZ monotherapy. Two of the patients with Crohn's disease required combination treatment throughout follow-up to obtain sustained remission. CONCLUSION Our findings suggest that combination treatment with anti TNF-α and VDZ is safe and might represent a long-term treatment option in selected patients.
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Affiliation(s)
- Lydia C T Buer
- Department of Gastroenterology, Oslo University Hospital.,Faculty of Medicine, University of Oslo
| | - Marte L Høivik
- Department of Gastroenterology, Oslo University Hospital
| | - David J Warren
- Department of Medical Biochemistry, Oslo University Hospital
| | - Asle W Medhus
- Department of Gastroenterology, Oslo University Hospital
| | - Bjørn A Moum
- Department of Gastroenterology, Oslo University Hospital.,Faculty of Medicine, University of Oslo
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30
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Ben-Horin S, Ungar B, Kopylov U, Lahat A, Yavzori M, Fudim E, Picard O, Peled Y, Eliakim R, Del Tedesco E, Paul S, Roblin X. Safety, efficacy and pharmacokinetics of vedolizumab in patients with simultaneous exposure to an anti-tumour necrosis factor. Aliment Pharmacol Ther 2018; 47:1117-1125. [PMID: 29446098 DOI: 10.1111/apt.14567] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 12/28/2017] [Accepted: 01/25/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND Data on combination-biologic treatment in (IBD) are still scant. AIM To explore outcomes of patients co-exposed to anti-TNF and vedolizumab. METHODS Patients starting vedolizumab having measurable anti-TNF levels after recently stopping adalimumab/infliximab ('VDZ-aTNF' group), were compared with control vedolizumab patients in a retrospective 1:2 matched case-control study. RESULTS Seventy-five patients were included (25 VDZ-aTNF, 50 VDZ). Adverse events were experienced by 9/25 VDZ-aTNF compared to 13/50 VDZ patients (P = 0.4, follow-up 14 weeks in all). Week 14 clinical remission was attained in 10/25 (40%) of VDZ-aTNF patients versus 23/50 (46%) of VDZ patients (OR = 0.8, 95% CI 0.3-2.1, P = 0.6) and clinical response in 19/25 (76%) versus 39/50 (78%) respectively (OR = 0.9, 95% CI 0.3-2.7, P = 0.8). Corticosteroid-free remission and corticosteroid-free response were experienced by 30% and 54%, respectively, of the entire cohort, and were similar between the two groups. Vedolizumab drug concentrations at week 2, 6 and 14 were similar among VDZ-aTNF and VDZ patients (P > 0.5). Multi-variable analysis showed independent association of some vedolizumab drug-levels time-points with baseline albumin and weight, but not with anti-TNF co-exposure. In a prospective study of a separate cohort of patients starting infliximab (n = 12), the percentage of α4β7+ memory T cells, slightly but nonsignificantly increased throughout weeks 0, 2 to 14 (26 ± 2.3%, 27.8 ± 2.9%, 29.5 ± 2.6% respectively, P = 0.06). CONCLUSIONS Vedolizumab/anti-TNF co-exposure did not generate new safety signals during 14-weeks induction, nor did it reduce efficacy or alter vedolizumab pharmacokinetics. These observations may aid the design of future co-biologics trials and also suggest that a deliberate waiting-interval between anti-TNF cessation and subsequent vedolizumab initiation may not be warranted.
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Affiliation(s)
- S Ben-Horin
- Department of Gastroenterology, Sackler School of Medicine, Sheba Medical Center Tel Hashomer, Tel-Aviv University, Tel Aviv, Israel.,First Affiliated Hospital of Sun-Yatsen University, Guangzhou, China
| | - B Ungar
- Department of Gastroenterology, Sackler School of Medicine, Sheba Medical Center Tel Hashomer, Tel-Aviv University, Tel Aviv, Israel
| | - U Kopylov
- Department of Gastroenterology, Sackler School of Medicine, Sheba Medical Center Tel Hashomer, Tel-Aviv University, Tel Aviv, Israel
| | - A Lahat
- Department of Gastroenterology, Sackler School of Medicine, Sheba Medical Center Tel Hashomer, Tel-Aviv University, Tel Aviv, Israel
| | - M Yavzori
- Department of Gastroenterology, Sackler School of Medicine, Sheba Medical Center Tel Hashomer, Tel-Aviv University, Tel Aviv, Israel
| | - E Fudim
- Department of Gastroenterology, Sackler School of Medicine, Sheba Medical Center Tel Hashomer, Tel-Aviv University, Tel Aviv, Israel
| | - O Picard
- Department of Gastroenterology, Sackler School of Medicine, Sheba Medical Center Tel Hashomer, Tel-Aviv University, Tel Aviv, Israel
| | - Y Peled
- Cardiology Department, Sheba Medical Center & Tel-Aviv University, Israel
| | - R Eliakim
- Department of Gastroenterology, Sackler School of Medicine, Sheba Medical Center Tel Hashomer, Tel-Aviv University, Tel Aviv, Israel
| | - E Del Tedesco
- Department of Gastroenterology, University Hospital of Saint Etienne, Saint Etienne, France
| | - S Paul
- Department of Gastroenterology, University Hospital of Saint Etienne, Saint Etienne, France
| | - X Roblin
- Department of Gastroenterology, University Hospital of Saint Etienne, Saint Etienne, France
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31
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A Challenging Case of Severe Ulcerative Colitis following the Initiation of Secukinumab for Ankylosing Spondylitis. Case Rep Gastrointest Med 2018; 2018:9679287. [PMID: 29666723 PMCID: PMC5832071 DOI: 10.1155/2018/9679287] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 01/18/2018] [Indexed: 01/11/2023] Open
Abstract
Secukinumab is an interleukin-17 inhibitor used for the treatment of ankylosing spondylitis (AS), psoriasis, and psoriatic arthritis. The risk of exacerbating underlying inflammatory bowel disease (IBD) in patients being treated with secukinumab for other conditions is controversial. We document a patient with AS and previously undiagnosed IBD, found to be in a severe ulcerative colitis flare shortly after receiving the loading dose of secukinumab. There are no guidelines regarding biologic salvage therapy for IBD in the setting of active treatment with another biologic agent. After waiting one half-life of secukinumab, our patient had an excellent response to initiation of infliximab.
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32
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Hindryckx P, Vande Casteele N, Novak G, Khanna R, D'Haens G, Sandborn WJ, Danese S, Jairath V, Feagan BG. The Expanding Therapeutic Armamentarium for Inflammatory Bowel Disease: How to Choose the Right Drug[s] for Our Patients? J Crohns Colitis 2018; 12:105-119. [PMID: 28961959 DOI: 10.1093/ecco-jcc/jjx117] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Accepted: 08/22/2017] [Indexed: 12/14/2022]
Abstract
The therapeutic landscape for inflammatory bowel disease [IBD] is rapidly evolving. Two new biologic drugs, vedolizumab and ustekinumab, have recently entered the marketplace, the first biosimilars have been introduced, and several other agents are at an advanced stage of clinical development. In parallel, therapeutic goals have shifted from symptom control towards mucosal healing and prevention of bowel damage. In the coming years, gastroenterologists will be faced with unprecedented choices when selecting the best treatment for their patients with IBD. In this article, we review existing data on the mechanisms of action, efficacy, and safety of recently approved and late-stage pipeline therapies, and use this information to speculate on the positioning of these drugs, alone or in combination, in therapeutic algorithms for Crohn's disease and ulcerative colitis.
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Affiliation(s)
- Pieter Hindryckx
- Robarts Clinical Trials, Inc., University of Western Ontario, London, ON, Canada.,Department of Gastroenterology, University of Ghent, Ghent, Belgium
| | - Niels Vande Casteele
- Robarts Clinical Trials, Inc., University of Western Ontario, London, ON, Canada.,Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
| | - Gregor Novak
- Robarts Clinical Trials, Inc., University of Western Ontario, London, ON, Canada.,Department of Gastroenterology, Ljubljana University Medical Centre, Ljubljana, Slovenia
| | - Reena Khanna
- Robarts Clinical Trials, Inc., University of Western Ontario, London, ON, Canada.,Department of Medicine, University of Western Ontario, London, ON, Canada
| | - Geert D'Haens
- Robarts Clinical Trials, Inc., University of Western Ontario, London, ON, Canada.,Inflammatory Bowel Disease Centre, Academic Medical Centre, Amsterdam, The Netherlands
| | - William J Sandborn
- Robarts Clinical Trials, Inc., University of Western Ontario, London, ON, Canada.,Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
| | - Silvio Danese
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Vipul Jairath
- Robarts Clinical Trials, Inc., University of Western Ontario, London, ON, Canada.,Department of Medicine, University of Western Ontario, London, ON, Canada.,Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada
| | - Brian G Feagan
- Robarts Clinical Trials, Inc., University of Western Ontario, London, ON, Canada.,Department of Medicine, University of Western Ontario, London, ON, Canada.,Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada
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33
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Ustekinumab and Vedolizumab Dual Biologic Therapy in the Treatment of Crohn's Disease. Case Rep Med 2017; 2017:5264216. [PMID: 29250117 PMCID: PMC5698793 DOI: 10.1155/2017/5264216] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Accepted: 10/15/2017] [Indexed: 11/24/2022] Open
Abstract
We present a case of refractory ileocolonic Crohn's disease in a 27-year-old female treated with dual ustekinumab and vedolizumab biologic therapy. She had mucosal healing for the first time in 13 years after a 10-month treatment of ustekinumab overlapped with 6 months of vedolizumab. No side effects were observed during the 6 months of dual biologic therapy. Short-term dual biologic therapy may be considered as a treatment option for induction of remission in refractory cases of Crohn's disease.
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34
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Fischer S, Rath T, Geppert CI, Manger B, Schett G, Neurath MF, Atreya R. Long-term Combination Therapy with Anti-TNF plus Vedolizumab Induces and Maintains Remission in Therapy-refractory Ulcerative Colitis. Am J Gastroenterol 2017; 112:1621-1623. [PMID: 28978957 DOI: 10.1038/ajg.2017.242] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Sarah Fischer
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nìrnberg, Erlangen, Germany
| | - Timo Rath
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nìrnberg, Erlangen, Germany
| | - Carol-Immanuel Geppert
- Department of Pathology, Friedrich-Alexander-Universität Erlangen-Nìrnberg, Erlangen, Germany
| | - Bernhard Manger
- Department of Medicine 3, Friedrich-Alexander-Universität Erlangen-Nìrnberg, Erlangen, Germany
| | - Georg Schett
- Department of Medicine 3, Friedrich-Alexander-Universität Erlangen-Nìrnberg, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nìrnberg, Erlangen, Germany
| | - Raja Atreya
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nìrnberg, Erlangen, Germany
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35
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Bethge J, Meffert S, Ellrichmann M, Conrad C, Nikolaus S, Schreiber S. Combination therapy with vedolizumab and etanercept in a patient with pouchitis and spondylarthritis. BMJ Open Gastroenterol 2017; 4:e000127. [PMID: 28243458 PMCID: PMC5306500 DOI: 10.1136/bmjgast-2016-000127] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Revised: 12/15/2016] [Accepted: 12/20/2016] [Indexed: 12/11/2022] Open
Abstract
Inflammatory bowel disease is frequently associated with spondylarthritis (SpA). It has been discussed that α4/β7 expressing lymphocytes are involved in the aetiology of SpA. We report a case of a successful combination therapy of vedolizumab (VDZ) and etanercept (ETA) in a patient with ulcerative colitis with pouchitis and SpA. In our case VDZ was effective for pouchitis and ineffective for SpA. The combination with ETA might be a useful treatment strategy to control both diseases and first indications suggest that it is safe. α4/β7 Expressing lymphocytes are most likely not associated in the aetiology of SpA.
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Affiliation(s)
- Johannes Bethge
- Medical Department I, Gastroenterology , University Medical Center, Schleswig Holstein, Campus Kiel , Kiel , Germany
| | - Silvia Meffert
- Medical Department I, Gastroenterology , University Medical Center, Schleswig Holstein, Campus Kiel , Kiel , Germany
| | - Mark Ellrichmann
- Medical Department I, Gastroenterology , University Medical Center, Schleswig Holstein, Campus Kiel , Kiel , Germany
| | - Claudio Conrad
- Medical Department I, Gastroenterology , University Medical Center, Schleswig Holstein, Campus Kiel , Kiel , Germany
| | - Susanna Nikolaus
- Medical Department I, Gastroenterology , University Medical Center, Schleswig Holstein, Campus Kiel , Kiel , Germany
| | - Stefan Schreiber
- Medical Department I, Gastroenterology , University Medical Center, Schleswig Holstein, Campus Kiel , Kiel , Germany
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36
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Abstract
Tumor necrosis factor (TNF) antagonists are the cornerstone of therapy for moderately to severely active inflammatory bowel disease (IBD). Although our understanding of pharmacokinetics, pharmacodynamics, and treatment optimization for these agents has evolved considerably over the past decade, a substantial majority of individuals fail to respond or lose response to TNF-antagonists over time. A need therefore remains for efficacious treatment options in these patients. Alternative immunological targets have now been identified, and several novel therapeutic agents are in development for IBD. In this review article, we discuss these novel therapeutic agents, with a particular focus on those demonstrated to be efficacious in phase 2 and 3 clinical trials. We further discuss considerations to be made when integrating these agents into routine practice over the next decade.
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Affiliation(s)
- Parambir S Dulai
- Division of Gastroenterology, University of California at San Diego, La Jolla, CA, USA
| | - William J Sandborn
- Division of Gastroenterology, University of California at San Diego, La Jolla, CA, USA.
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37
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Peyrin-Biroulet L, Van Assche G, Gómez-Ulloa D, García-Álvarez L, Lara N, Black CM, Kachroo S. Systematic Review of Tumor Necrosis Factor Antagonists in Extraintestinal Manifestations in Inflammatory Bowel Disease. Clin Gastroenterol Hepatol 2017; 15:25-36.e27. [PMID: 27392760 DOI: 10.1016/j.cgh.2016.06.025] [Citation(s) in RCA: 91] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Revised: 06/15/2016] [Accepted: 06/25/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS This systematic review investigated the efficacy and the effectiveness of biologic drugs in extraintestinal manifestations (EIMs) in inflammatory bowel disease (IBD). METHODS Literature search was conducted in PubMed, Embase, and Cochrane until October 2015. Main inclusion criteria were adults with IBD, use of a biologic drug, evolution of EIMs, interventional study, or non-interventional study. RESULTS Nine interventional studies (2 randomized controlled trials [N = 797], 7 open label trials [N = 1143], and 13 non-interventional studies [N = 914]) were included. Tumor necrosis factor (TNF) antagonists achieved complete response for pyoderma gangrenosum in 21%-25% of patients in interventional studies and in 92%-100% patients in non-interventional studies, with similar results for other cutaneous manifestations such as erythema nodosum or stomatitis. Adalimumab significantly reduced the prevalence of anemia vs placebo after 56 weeks in 1 randomized controlled trial. In 2 non-interventional studies, anti-TNF therapy improved anemia in the short-term (67%) and in the long-term (34%). Complete response after anti-TNF treatment was reported in interventional studies, including arthralgia (reduction in prevalence from 47.1% to 26.8% in the mid-term in 1 open label trial) and arthritis (reduction in prevalence from 8.7% to 2.1% and from 58% to 12.5% in 2 open label trials). Anti-TNFs were beneficial for a majority of patients with ocular manifestations. Infliximab was associated with improved outcomes in bone formation and bone mineral density. CONCLUSIONS Anti-TNFs appear to be effective alternatives for certain EIMs associated with IBD including musculoskeletal, cutaneous, and ocular manifestations, and some beneficial effect may be obtained in metabolic bone disease and on hematologic or vascular EIMs.
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Affiliation(s)
| | - Gert Van Assche
- Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium
| | | | | | - Núria Lara
- IMS Health, Real-World Evidence Solutions, Barcelona, Spain
| | - Chris M Black
- Center for Observational and Real-World Evidence (CORE), Merck and Co, Inc, Kenilworth, New Jersey
| | - Sumesh Kachroo
- Center for Observational and Real-World Evidence (CORE), Merck and Co, Inc, Kenilworth, New Jersey
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38
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Yzet C, Dupas JL, Fumery M. Ustekinumab and Anti-TNF Combination Therapy in Patients with Inflammatory Bowel Disease. Am J Gastroenterol 2016; 111:748-9. [PMID: 27151127 DOI: 10.1038/ajg.2016.66] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Clara Yzet
- Service d'Hépato-Gastroentérologie, Centre Hospitalier Universitaire Amiens-Picardie, Avenue Laennec-Salouel, Amiens, France
| | - Jean-Louis Dupas
- Service d'Hépato-Gastroentérologie, Centre Hospitalier Universitaire Amiens-Picardie, Avenue Laennec-Salouel, Amiens, France
| | - Mathurin Fumery
- Service d'Hépato-Gastroentérologie, Centre Hospitalier Universitaire Amiens-Picardie, Avenue Laennec-Salouel, Amiens, France
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