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Giordano A, Rovira M, Veny M, Barastegui R, Marín P, Martínez C, Fernández-Avilés F, Suárez-Lledó M, Domènech A, Serrahima A, Lozano M, Cid J, Ordás I, Fernández-Clotet A, Caballol B, Gallego M, Vara A, Masamunt MC, Giner À, Teubel I, Esteller M, Corraliza AM, Panés J, Salas A, Ricart E. Cyclophosphamide-free Mobilisation Increases Safety While Preserving the Efficacy of Autologous Haematopoietic Stem Cell Transplantation in Refractory Crohn's Disease Patients. J Crohns Colitis 2024; 18:1701-1712. [PMID: 38757210 DOI: 10.1093/ecco-jcc/jjae076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 05/07/2024] [Accepted: 05/16/2024] [Indexed: 05/18/2024]
Abstract
BACKGROUND AND AIM Autologous haematopoietic stem cell transplantation [AHSCT] is a therapeutic option for refractory Crohn's disease [CD]. However, high adverse event rates related to chemotherapy toxicity and immunosuppression limit its applicability. This study aims to evaluate AHSCT's safety and efficacy using a cyclophosphamide [Cy]-free mobilisation regimen. METHODS A prospective, observational study included 14 refractory CD patients undergoing AHSCT between June 2017 and October 2022. The protocol involved outpatient mobilisation with G-CSF 12-16 μg/kg/daily for 5 days, and optional Plerixafor 240 μg/d [1-2 doses] if the CD34 + cell count target was unmet. Standard conditioning with Cy and anti-thymocyte globulin was administered. Clinical, endoscopic, and radiological assessments were conducted at baseline and during follow-up. RESULTS All patients achieved successful outpatient mobilisation [seven patients needed Plerixafor] and underwent transplantation. Median follow-up was 106 weeks (interquartile range [IQR] 52-348). No mobilisation-related serious adverse events [SAEs] or CD worsening occurred. Clinical and endoscopic remission rates were 71% and 41.7% at 26 weeks, 64% and 25% at 52 weeks, and 71% and 16.7% at the last follow-up, respectively. The percentage of patients who restarted CD therapy for clinical relapse and/or endoscopic/radiological activity was 14% at 26 weeks, 57% at 52 weeks, and 86% at the last follow-up, respectively. Peripheral blood cell populations and antibody levels post-AHSCT were comparable to Cy-based mobilisation. CONCLUSIONS Cy-free mobilisation is safe and feasible in refractory CD patients undergoing AHSCT. Although relapse occurs in a significant proportion of patients, clinical and endoscopic responses are achieved upon CD-specific therapy reintroduction.
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Affiliation(s)
- Antonio Giordano
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Montserrat Rovira
- Bone Marrow Transplantation Unit, Haematology Department, Institute of Haematology and Oncology Hospital Clínic Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], University of Barcelona, Josep Carreras Leukaemia Research Foundation, Barcelona, Catalonia, Spain
| | - Marisol Veny
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Rebeca Barastegui
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Pedro Marín
- Bone Marrow Transplantation Unit, Haematology Department, Institute of Haematology and Oncology Hospital Clínic Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], University of Barcelona, Josep Carreras Leukaemia Research Foundation, Barcelona, Catalonia, Spain
| | - Carmen Martínez
- Bone Marrow Transplantation Unit, Haematology Department, Institute of Haematology and Oncology Hospital Clínic Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], University of Barcelona, Josep Carreras Leukaemia Research Foundation, Barcelona, Catalonia, Spain
| | - Francesc Fernández-Avilés
- Bone Marrow Transplantation Unit, Haematology Department, Institute of Haematology and Oncology Hospital Clínic Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], University of Barcelona, Josep Carreras Leukaemia Research Foundation, Barcelona, Catalonia, Spain
| | - María Suárez-Lledó
- Bone Marrow Transplantation Unit, Haematology Department, Institute of Haematology and Oncology Hospital Clínic Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], University of Barcelona, Josep Carreras Leukaemia Research Foundation, Barcelona, Catalonia, Spain
| | - Ariadna Domènech
- Bone Marrow Transplantation Unit, Haematology Department, Institute of Haematology and Oncology Hospital Clínic Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], University of Barcelona, Josep Carreras Leukaemia Research Foundation, Barcelona, Catalonia, Spain
| | - Anna Serrahima
- Bone Marrow Transplantation Unit, Haematology Department, Institute of Haematology and Oncology Hospital Clínic Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], University of Barcelona, Josep Carreras Leukaemia Research Foundation, Barcelona, Catalonia, Spain
| | - Miquel Lozano
- Apheresis Unit, Department of Hemotherapy and Hemostasis, ICAMS, Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Catalonia, Spain
| | - Joan Cid
- Apheresis Unit, Department of Hemotherapy and Hemostasis, ICAMS, Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Catalonia, Spain
| | - Ingrid Ordás
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Agnés Fernández-Clotet
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Berta Caballol
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Marta Gallego
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Alejandro Vara
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Maria Carme Masamunt
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Àngel Giner
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Iris Teubel
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Miriam Esteller
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Anna María Corraliza
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Julian Panés
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Azucena Salas
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
| | - Elena Ricart
- Inflammatory Bowel Disease Unit, Gastroenterology Department. Hospital Clínic Barcelona, Fundació Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Barcelona, Catalonia, Spain
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Smith B, Smith H, Machini M. Novel Pharmaceuticals and Therapeutics for Tumor Necrosis Factor-Alpha-Resistant Crohn's Disease: A Narrative Review. Cureus 2024; 16:e65357. [PMID: 39184689 PMCID: PMC11344558 DOI: 10.7759/cureus.65357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 07/24/2024] [Indexed: 08/27/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a medical condition that causes persistent, relapsing inflammation of the gastrointestinal tract. It is an umbrella term encompassing two different conditions: ulcerative colitis (UC) and Crohn's disease (CD). The standard treatment for patients with moderate to severe CD is tumor necrosis factor-α (TNF-α) inhibitors; however, a subset of CD patients face challenges in regard to this disease's treatment. Certain populations of patients with CD may exhibit resistance or develop tolerance to TNF-α inhibitor therapy over time. The recurrent gastrointestinal inflammation associated with CD can severely impact the quality of life and lead to complications for those suffering from this condition. The symptomatic flare-ups these subpopulations continue to experience underscores why such a need for alternative therapies is desperately needed. These alternative therapies not only offer potential benefits for those with TNF-α resistance, but CD may also serve as a superior therapy option for those trying to avoid the adverse effects of CD treatments available today. This review aims to explore and investigate the novel drugs and therapies that are being investigated for the treatment of TNF-α resistant CD, such as upadacitinib, risankizumab, vedolizumab, synbiotics, fecal microbiota transplantation (FMT), and stem cell therapy. Upadacitinib is a Janus kinase inhibitor, Risankizumab is a monoclonal antibody targeting interleukin-23, and Vedolizumab is an integrin receptor antagonist. The latest advancements in CD management have shown encouraging results. Some of these novel drugs and therapies not only offer a potential solution for CD patients exhibiting resistance to TNF-α inhibitors but may also provide a superior alternative for individuals prone to opportunistic infections.
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Affiliation(s)
- Blake Smith
- Medical School, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Fort Lauderdale, USA
| | - Haylie Smith
- Medical School, Edward Via College of Osteopathic Medicine, Spartanburg, USA
| | - Matthew Machini
- Foundational Sciences, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Clearwater, USA
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Dias IE, Dias IR, Franchi-Mendes T, Viegas CA, Carvalho PP. A Comprehensive Exploration of Therapeutic Strategies in Inflammatory Bowel Diseases: Insights from Human and Animal Studies. Biomedicines 2024; 12:735. [PMID: 38672091 PMCID: PMC11048724 DOI: 10.3390/biomedicines12040735] [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: 12/14/2023] [Revised: 02/20/2024] [Accepted: 03/01/2024] [Indexed: 04/28/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a collective term for a group of chronic inflammatory enteropathies which are characterized by intestinal inflammation and persistent or frequent gastrointestinal signs. This disease affects more than 3.5 million humans worldwide and presents some similarities between animal species, in particular, dogs and cats. Although the underlying mechanism that triggers the disease is not yet well understood, the evidence suggests a multifactorial etiology implicating genetic causes, environmental factors, microbiota imbalance, and mucosa immune defects, both in humans and in dogs and cats. Conventional immunomodulatory drug therapies, such as glucocorticoids or immunosuppressants, are related with numerous adverse effects that limit its long-term use, creating the need to develop new therapeutic strategies. Mesenchymal stromal cells (MSCs) emerge as a promising alternative that attenuates intestinal inflammation by modulating inflammatory cytokines in inflamed tissues, and also due to their pro-angiogenic, anti-apoptotic, anti-fibrotic, regenerative, anti-tumor, and anti-microbial potential. However, this therapeutic approach may have important limitations regarding the lack of studies, namely in veterinary medicine, lack of standardized protocols, and high economic cost. This review summarizes the main differences and similarities between human, canine, and feline IBD, as well as the potential treatment and future prospects of MSCs.
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Affiliation(s)
- Inês Esteves Dias
- CITAB—Centre for the Research and Technology of Agro-Environmental and Biological Sciences, University of Trás-os-Montes e Alto Douro (UTAD), Quinta de Prados, 5000-801 Vila Real, Portugal; (I.E.D.); (I.R.D.)
- Inov4Agro—Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production, Quinta de Prados, 5000-801 Vila Real, Portugal
| | - Isabel Ribeiro Dias
- CITAB—Centre for the Research and Technology of Agro-Environmental and Biological Sciences, University of Trás-os-Montes e Alto Douro (UTAD), Quinta de Prados, 5000-801 Vila Real, Portugal; (I.E.D.); (I.R.D.)
- Inov4Agro—Institute for Innovation, Capacity Building and Sustainability of Agri-Food Production, Quinta de Prados, 5000-801 Vila Real, Portugal
- Department of Veterinary Sciences, School of Agricultural and Veterinary Sciences (ECAV), University of Trás-os-Montes e Alto Douro (UTAD), Quinta de Prados, 5000-801 Vila Real, Portugal
- CECAV—Centre for Animal Sciences and Veterinary Studies, University of Trás-os-Montes e Alto Douro (UTAD), Quinta de Prados, 5000-801 Vila Real, Portugal
- AL4AnimalS—Associate Laboratory for Animal and Veterinary Sciences, Quinta de Prados, 5000-801 Vila Real, Portugal
| | - Teresa Franchi-Mendes
- Department of Bioengineering and IBB—Institute for Bioengineering and Biosciences at Instituto Superior Técnico, University of Lisbon, Av. Rovisco Pais, 1049-001 Lisboa, Portugal;
- Associate Laboratory i4HB—Institute for Health and Bioeconomy at Instituto Superior Técnico, University of Lisbon, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
| | - Carlos Antunes Viegas
- Department of Veterinary Sciences, School of Agricultural and Veterinary Sciences (ECAV), University of Trás-os-Montes e Alto Douro (UTAD), Quinta de Prados, 5000-801 Vila Real, Portugal
- CECAV—Centre for Animal Sciences and Veterinary Studies, University of Trás-os-Montes e Alto Douro (UTAD), Quinta de Prados, 5000-801 Vila Real, Portugal
- AL4AnimalS—Associate Laboratory for Animal and Veterinary Sciences, Quinta de Prados, 5000-801 Vila Real, Portugal
- CIVG—Vasco da Gama Research Center, University School Vasco da Gama (EUVG), Campus Universitário, Av. José R. Sousa Fernandes, Lordemão, 3020-210 Coimbra, Portugal;
| | - Pedro Pires Carvalho
- CIVG—Vasco da Gama Research Center, University School Vasco da Gama (EUVG), Campus Universitário, Av. José R. Sousa Fernandes, Lordemão, 3020-210 Coimbra, Portugal;
- Vetherapy—Research and Development in Biotechnology, 3020-210 Coimbra, Portugal
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Tian CM, Zhang Y, Yang MF, Xu HM, Zhu MZ, Yao J, Wang LS, Liang YJ, Li DF. Stem Cell Therapy in Inflammatory Bowel Disease: A Review of Achievements and Challenges. J Inflamm Res 2023; 16:2089-2119. [PMID: 37215379 PMCID: PMC10199681 DOI: 10.2147/jir.s400447] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 05/03/2023] [Indexed: 05/24/2023] Open
Abstract
Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a group of chronic inflammatory diseases of the gastrointestinal tract. Repeated inflammation can lead to complications, such as intestinal fistula, obstruction, perforation, and bleeding. Unfortunately, achieving durable remission and mucosal healing (MH) with current treatments is difficult. Stem cells (SCs) have the potential to modulate immunity, suppress inflammation, and have anti-apoptotic and pro-angiogenic effects, making them an ideal therapeutic strategy to target chronic inflammation and intestinal damage in IBD. In recent years, hematopoietic stem cells (HSCs) and adult mesenchymal stem cells (MSCs) have shown efficacy in treating IBD. In addition, numerous clinical trials have evaluated the efficiency of MSCs in treating the disease. This review summarizes the current research progress on the safety and efficacy of SC-based therapy for IBD in both preclinical models and clinical trials. We discuss potential mechanisms of SC therapy, including tissue repair, paracrine effects, and the promotion of angiogenesis, immune regulation, and anti-inflammatory effects. We also summarize current SC engineering strategies aimed at enhancing the immunosuppressive and regenerative capabilities of SCs for treating intestinal diseases. Additionally, we highlight current limitations and future perspectives of SC-related therapy for IBD.
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Affiliation(s)
- Cheng-Mei Tian
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
- Department of Emergency, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - Yuan Zhang
- Department of Medical Administration, Huizhou Institute of Occupational Diseases Control and Prevention, Huizhou, Guangdong, People’s Republic of China
| | - Mei-Feng Yang
- Department of Hematology, Yantian District People’s Hospital, Shenzhen, Guangdong, People’s Republic of China
| | - Hao-Ming Xu
- Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, People’s Republic of China
| | - Min-Zheng Zhu
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, People’s Republic of China
| | - Jun Yao
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - Li-Sheng Wang
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - Yu-Jie Liang
- Department of Child and Adolescent Psychiatry, Shenzhen Kangning Hospital, Shenzhen, Guangdong, People’s Republic of China
| | - De-Feng Li
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
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Reider S, Binder L, Fürst S, Hatzl S, Blesl A. Hematopoietic Stem Cell Transplantation in Refractory Crohn's Disease: Should It Be Considered? Cells 2022; 11:3463. [PMID: 36359859 PMCID: PMC9656531 DOI: 10.3390/cells11213463] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 10/29/2022] [Accepted: 10/31/2022] [Indexed: 08/06/2023] Open
Abstract
Hematopoietic stem cell transplantation (HSCT) is widely used in benign and malignant hematological diseases. During the last decade, HSCT, mainly autologous, also gained increasing attention in the treatment of refractory autoimmune diseases. Crohn's disease (CD) is an inflammatory bowel disease leading to transmural inflammation potentially affecting all parts of the luminal gastrointestinal tract. Despite improving therapeutic options, including various biologics, some patients are refractory to all lines of available conservative therapy, leading to increased morbidity and reduced quality of life. Apart from surgery, HSCT might be a reasonable treatment alternative for refractory CD patients. This review aims to describe the current role of HSCT in CD and discusses the procedure, the correct patient selection, the clinical efficacy from initial remission to following relapse rates, and complications of this treatment.
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Affiliation(s)
- Simon Reider
- Christian Doppler Laboratory for Mucosal Immunology, Johannes Kepler University Linz, 4020 Linz, Austria
- Department of Internal Medicine 2 (Gastroenterology and Hepatology), Faculty of Medicine, Kepler University Hospital, Johannes Kepler University, 4020 Linz, Austria
| | - Lukas Binder
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria
| | - Stefan Fürst
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria
| | - Stefan Hatzl
- Intensive Care Unit, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria
- Division of Hematology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria
| | - Andreas Blesl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria
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Hoang DM, Pham PT, Bach TQ, Ngo ATL, Nguyen QT, Phan TTK, Nguyen GH, Le PTT, Hoang VT, Forsyth NR, Heke M, Nguyen LT. Stem cell-based therapy for human diseases. Signal Transduct Target Ther 2022; 7:272. [PMID: 35933430 PMCID: PMC9357075 DOI: 10.1038/s41392-022-01134-4] [Citation(s) in RCA: 435] [Impact Index Per Article: 145.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 07/19/2022] [Accepted: 07/21/2022] [Indexed: 02/07/2023] Open
Abstract
Recent advancements in stem cell technology open a new door for patients suffering from diseases and disorders that have yet to be treated. Stem cell-based therapy, including human pluripotent stem cells (hPSCs) and multipotent mesenchymal stem cells (MSCs), has recently emerged as a key player in regenerative medicine. hPSCs are defined as self-renewable cell types conferring the ability to differentiate into various cellular phenotypes of the human body, including three germ layers. MSCs are multipotent progenitor cells possessing self-renewal ability (limited in vitro) and differentiation potential into mesenchymal lineages, according to the International Society for Cell and Gene Therapy (ISCT). This review provides an update on recent clinical applications using either hPSCs or MSCs derived from bone marrow (BM), adipose tissue (AT), or the umbilical cord (UC) for the treatment of human diseases, including neurological disorders, pulmonary dysfunctions, metabolic/endocrine-related diseases, reproductive disorders, skin burns, and cardiovascular conditions. Moreover, we discuss our own clinical trial experiences on targeted therapies using MSCs in a clinical setting, and we propose and discuss the MSC tissue origin concept and how MSC origin may contribute to the role of MSCs in downstream applications, with the ultimate objective of facilitating translational research in regenerative medicine into clinical applications. The mechanisms discussed here support the proposed hypothesis that BM-MSCs are potentially good candidates for brain and spinal cord injury treatment, AT-MSCs are potentially good candidates for reproductive disorder treatment and skin regeneration, and UC-MSCs are potentially good candidates for pulmonary disease and acute respiratory distress syndrome treatment.
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Affiliation(s)
- Duc M Hoang
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam.
| | - Phuong T Pham
- Department of Cellular Therapy, Vinmec High-Tech Center, Vinmec Healthcare System, Hanoi, Vietnam
| | - Trung Q Bach
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Anh T L Ngo
- Department of Cellular Therapy, Vinmec High-Tech Center, Vinmec Healthcare System, Hanoi, Vietnam
| | - Quyen T Nguyen
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Trang T K Phan
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Giang H Nguyen
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Phuong T T Le
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Van T Hoang
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Nicholas R Forsyth
- Institute for Science & Technology in Medicine, Keele University, Keele, UK
| | - Michael Heke
- Department of Biology, Stanford University, Stanford, CA, USA
| | - Liem Thanh Nguyen
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
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Zhang HM, Yuan S, Meng H, Hou XT, Li J, Xue JC, Li Y, Wang Q, Nan JX, Jin XJ, Zhang QG. Stem Cell-Based Therapies for Inflammatory Bowel Disease. Int J Mol Sci 2022; 23:8494. [PMID: 35955628 PMCID: PMC9368934 DOI: 10.3390/ijms23158494] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/27/2022] [Accepted: 07/28/2022] [Indexed: 11/23/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic, relapsing disease that severely affects patients' quality of life. The exact cause of IBD is uncertain, but current studies suggest that abnormal activation of the immune system, genetic susceptibility, and altered intestinal flora due to mucosal barrier defects may play an essential role in the pathogenesis of IBD. Unfortunately, IBD is currently difficult to be wholly cured. Thus, more treatment options are needed for different patients. Stem cell therapy, mainly including hematopoietic stem cell therapy and mesenchymal stem cell therapy, has shown the potential to improve the clinical disease activity of patients when conventional treatments are not effective. Stem cell therapy, an emerging therapy for IBD, can alleviate mucosal inflammation through mechanisms such as immunomodulation and colonization repair. Clinical studies have confirmed the effectiveness of stem cell transplantation in refractory IBD and the ability to maintain long-term remission in some patients. However, stem cell therapy is still in the research stage, and its safety and long-term efficacy remain to be further evaluated. This article reviews the upcoming stem cell transplantation methods for clinical application and the results of ongoing clinical trials to provide ideas for the clinical use of stem cell transplantation as a potential treatment for IBD.
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Affiliation(s)
- Hua-Min Zhang
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, China; (H.-M.Z.); (S.Y.); (J.-X.N.)
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China; (H.M.); (X.-T.H.); (J.L.); (J.-C.X.); (Y.L.); (Q.W.)
| | - Shuo Yuan
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, China; (H.-M.Z.); (S.Y.); (J.-X.N.)
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China; (H.M.); (X.-T.H.); (J.L.); (J.-C.X.); (Y.L.); (Q.W.)
| | - Huan Meng
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China; (H.M.); (X.-T.H.); (J.L.); (J.-C.X.); (Y.L.); (Q.W.)
| | - Xiao-Ting Hou
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China; (H.M.); (X.-T.H.); (J.L.); (J.-C.X.); (Y.L.); (Q.W.)
| | - Jiao Li
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China; (H.M.); (X.-T.H.); (J.L.); (J.-C.X.); (Y.L.); (Q.W.)
- Department of Immunology and Pathogenic Biology, College of Basic Medicine, Yanbian University, Yanji 133002, China
| | - Jia-Chen Xue
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China; (H.M.); (X.-T.H.); (J.L.); (J.-C.X.); (Y.L.); (Q.W.)
- Department of Immunology and Pathogenic Biology, College of Basic Medicine, Yanbian University, Yanji 133002, China
| | - You Li
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China; (H.M.); (X.-T.H.); (J.L.); (J.-C.X.); (Y.L.); (Q.W.)
| | - Qi Wang
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China; (H.M.); (X.-T.H.); (J.L.); (J.-C.X.); (Y.L.); (Q.W.)
| | - Ji-Xing Nan
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, China; (H.-M.Z.); (S.Y.); (J.-X.N.)
| | - Xue-Jun Jin
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, China; (H.-M.Z.); (S.Y.); (J.-X.N.)
| | - Qing-Gao Zhang
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, China; (H.M.); (X.-T.H.); (J.L.); (J.-C.X.); (Y.L.); (Q.W.)
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Wang R, Yao Q, Chen W, Gao F, Li P, Wu J, Yu J, Cao H. Stem cell therapy for Crohn's disease: systematic review and meta-analysis of preclinical and clinical studies. Stem Cell Res Ther 2021; 12:463. [PMID: 34407875 PMCID: PMC8375136 DOI: 10.1186/s13287-021-02533-0] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Accepted: 08/02/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND We explored whether stem cell therapy was effective for animal models and patients with Crohn's disease (CD). METHODS We searched five online databases. The relative outcomes were analyzed with the aid of GetData Graph Digitizer 2.26 and Stata 16.0 software. The SYRCLE risk of bias tool and the MINORS tool were used to assess study quality. RESULTS We evaluated 46 studies including 28 animal works (n = 567) and 18 human trials (n = 360). In the animal studies, the disease activity index dramatically decreased in the mesenchymal stem cell (MSC) treatment groups compared to the control group. Rats and mice receiving MSCs exhibited longer colons [mice: standardized mean difference (SMD) 2.84, P = 0.000; rats: SMD 1.44, P = 0.029], lower histopathological scores (mice: SMD - 4.58, p = 0.000; rats: SMD - 1.41, P = 0.000) and lower myeloperoxidase levels (SMD - 6.22, P = 0.000). In clinical trials, stem cell transplantation reduced the CD activity index (SMD - 2.10, P = 0.000), the CD endoscopic index of severity (SMD - 3.40, P = 0.000) and simplified endoscopy score for CD (SMD - 1.71, P = 0.000) and improved the inflammatory bowel disease questionnaire score (SMD 1.33, P = 0.305) compared to control values. CD patients maintained high remission rates for 3-24 months after transplantation. CONCLUSIONS Stem cell transplantation is a valuable supplementary therapy for CD.
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Affiliation(s)
- Ruo Wang
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Qigu Yao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Wenyi Chen
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Feiqiong Gao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Pan Li
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Jian Wu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Jiong Yu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China
| | - Hongcui Cao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Rd., Hangzhou City, 310003, China.
- National Clinical Research Center for Infectious Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China.
- Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-Chemical Injury Diseases, 79 Qingchun Rd., Hangzhou City, 310003, China.
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Cassinotti A, Passamonti F, Segato S. CELL THERAPY IN INFLAMMATORY BOWEL DISEASE. Pharmacol Res 2021; 163:105247. [PMID: 33069755 DOI: 10.1016/j.phrs.2020.105247] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 10/06/2020] [Accepted: 10/07/2020] [Indexed: 12/14/2022]
Abstract
In recent years, cell-based therapies have been explored in various immune-mediated inflammatory diseases, including inflammatory bowel disease (IBD). Cell therapy is the process of introducing new cells into an organism or tissue in order to treat a disease. The most studied cellular treatment in IBD was "stem cells-based therapy", which was explored according to different protocols in terms of type of donors, stem cells sources, study design and clinical endpoints. More recently, preliminary studies have also described the clinical use of "regulatory cells", which include T-reg and Tr1 cells, and "tolerogenic" dendritic cells. Finally, induced pluripotent stem cells are the subject of an intensive preclinical research program on animal models, including those related to colitis.
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Affiliation(s)
| | | | - Sergio Segato
- Gastroenterology Unit, ASST Sette Laghi, Varese Italy
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10
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Oliveira MC, Elias JB, Moraes DAD, Simões BP, Rodrigues M, Ribeiro AAF, Piron-Ruiz L, Ruiz MA, Hamerschlak N. A review of hematopoietic stem cell transplantation for autoimmune diseases: multiple sclerosis, systemic sclerosis and Crohn's disease. Position paper of the Brazilian Society of Bone Marrow Transplantation. Hematol Transfus Cell Ther 2021; 43:65-86. [PMID: 32418777 PMCID: PMC7910166 DOI: 10.1016/j.htct.2020.03.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 03/19/2020] [Accepted: 03/23/2020] [Indexed: 12/16/2022] Open
Abstract
Autoimmune diseases are an important field for the development of bone marrow transplantation, or hematopoietic stem cell transplantation. In Europe alone, almost 3000 procedures have been registered so far. The Brazilian Society for Bone Marrow Transplantation (Sociedade Brasileira de Transplantes de Medula Óssea) organized consensus meetings for the Autoimmune Diseases Group, to review the available literature on hematopoietic stem cell transplantation for autoimmune diseases, aiming to gather data that support the procedure for these patients. Three autoimmune diseases for which there are evidence-based indications for hematopoietic stem cell transplantation are multiple sclerosis, systemic sclerosis and Crohn's disease. The professional stem cell transplant societies in America, Europe and Brazil (Sociedade Brasileira de Transplantes de Medula Óssea) currently consider hematopoietic stem cell transplantation as a therapeutic modality for these three autoimmune diseases. This article reviews the evidence available.
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Affiliation(s)
- Maria Carolina Oliveira
- Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (FMRP-USP), Ribeirão Preto, SP, Brazil
| | - Juliana Bernardes Elias
- Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (FMRP-USP), Ribeirão Preto, SP, Brazil
| | | | - Belinda Pinto Simões
- Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (FMRP-USP), Ribeirão Preto, SP, Brazil
| | | | | | - Lilian Piron-Ruiz
- Associação Portuguesa de Beneficência de São José do Rio Preto, São José do Rio Preto, SP, Brazil
| | - Milton Arthur Ruiz
- Associação Portuguesa de Beneficência de São José do Rio Preto, São José do Rio Preto, SP, Brazil
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11
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A pilot feasibility study of non-myeloablative allogeneic hematopoietic stem cell transplantation for refractory Crohn Disease. Bone Marrow Transplant 2020; 55:2343-2346. [PMID: 32467584 DOI: 10.1038/s41409-020-0953-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 05/05/2020] [Accepted: 05/14/2020] [Indexed: 01/21/2023]
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12
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Turse EP, Dailey FE, Naseer M, Partyka EK, Bragg JD, Tahan V. Stem cells for luminal, fistulizing, and perianal inflammatory bowel disease: a comprehensive updated review of the literature. Stem Cells Cloning 2018; 11:95-113. [PMID: 30568468 PMCID: PMC6267708 DOI: 10.2147/sccaa.s135414] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Much research has been performed over the last decade on stem cell therapy as treatment for patients with inflammatory bowel disease. Hematopoietic and mesenchymal stem cells, both allogeneic (from someone else) and autologous (from own patient), have been studied with safe and efficacious results in the majority of patients treated for luminal, perianal, and/or fistulizing disease. Here in this review, we highlight all human trials that have been conducted utilizing stem cell therapy treatment in patients with inflammatory bowel disease.
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Affiliation(s)
- Erica P Turse
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Missouri Health Center, Columbia, MO 65212, USA,
| | - Francis E Dailey
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Missouri Health Center, Columbia, MO 65212, USA,
| | - Maliha Naseer
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Missouri Health Center, Columbia, MO 65212, USA,
| | - Edward K Partyka
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Missouri Health Center, Columbia, MO 65212, USA,
| | - Jack D Bragg
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Missouri Health Center, Columbia, MO 65212, USA,
| | - Veysel Tahan
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Missouri Health Center, Columbia, MO 65212, USA,
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13
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Hernanz N, Sierra M, Volpato N, Núñez-Gómez L, Mesonero F, Herrera-Puente P, García-Gutiérrez V, Albillos A, López-San Román A. Autologous haematopoietic stem cell transplantation in refractory Crohn's disease: Experience in our centre. GASTROENTEROLOGIA Y HEPATOLOGIA 2018; 42:16-22. [PMID: 30337206 DOI: 10.1016/j.gastrohep.2018.08.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2018] [Revised: 07/16/2018] [Accepted: 08/21/2018] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Autologous haematopoietic stem cell transplantation (AHSCT) is an accepted treatment in refractory Crohn's disease (CD). MATERIAL AND METHODS Data on patients with refractory CD subjected to AHSCT are collected at the Hospital Universitario Ramón y Cajal in Madrid and the results obtained are described retrospectively. RESULTS Seven patients in total have received AHSCT due to refractory CD in our centre. Three patients (43%) presented with clinical and endoscopic remission; one patient (14%) clinical improvement without remission and three patients (43%) remained active with the need to restart treatment in the assessment of the initial response to the AHSCT (after six months). Symptoms recurred in five of the seven patients (71%) and all of them had to restart medical treatment after an average of 13.8 months (range: 3-30 months). Only one patient needed surgery after the AHSCT. At the end of the follow-up, after a mean of 48 months (range: 17-78 months), 5/7 (71%) of the patients were in clinical remission with or without treatment. CONCLUSION AHSCT may be a promising therapeutic option for patients with refractory CD. Its usefulness lies in the fact that it can produce clinical remission without treatment in some patients, but also that it can make the disease treatable, obtaining a response to certain treatments in patients who had previously lost it.
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Affiliation(s)
- Nerea Hernanz
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, Madrid, España
| | - María Sierra
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, Madrid, España
| | - Nadja Volpato
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, Madrid, España
| | - Laura Núñez-Gómez
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, Madrid, España
| | - Francisco Mesonero
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, Madrid, España
| | | | | | - Agustín Albillos
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, Madrid, España
| | - Antonio López-San Román
- Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, Madrid, España.
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14
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Brierley CK, Castilla-Llorente C, Labopin M, Badoglio M, Rovira M, Ricart E, Dierickx D, Vermeire S, Hasselblatt P, Finke J, Onida F, Cassinotti A, Satsangi J, Kazmi M, López-Sanromán A, Schmidt C, Farge D, Travis SPL, Hawkey CJ, Snowden JA. Autologous Haematopoietic Stem Cell Transplantation for Crohn's Disease: A Retrospective Survey of Long-term Outcomes From the European Society for Blood and Marrow Transplantation. J Crohns Colitis 2018; 12:1097-1103. [PMID: 29788233 PMCID: PMC6113702 DOI: 10.1093/ecco-jcc/jjy069] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 04/05/2018] [Accepted: 05/15/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Autologous haematopoietic stem cell transplantation [AHSCT] is a therapeutic option for patients with severe, treatment-refractory Crohn's disease [CD]. The evidence base for AHSCT for CD is limited, with one randomised trial [ASTIC] suggesting benefit. The aim of this study was to evaluate safety and efficacy for patients undergoing AHSCT for CD in Europe, outside the ASTIC trial. METHODS We identified 99 patients in the European Society for Blood and Marrow Transplantation [EBMT] registry, who were eligible for inclusion. Transplant and clinical outcomes were obtained for 82 patients from 19 centres in seven countries. RESULTS Median patient age was 30 years [range 20-65]. Patients had failed or been intolerant to a median of six lines of drug therapy; 61/82 [74%] had had surgery. Following AHSCT, 53/78 [68%] experienced complete remission or significant improvement in symptoms at a median follow-up of 41 months [range 6-174]; 22/82 [27%] required no medical therapy at any point post-AHSCT. In patients who had re-started medical therapy at latest follow-up, 57% [24/42] achieved remission or significant symptomatic improvement with therapies to which they had previously lost response or been non-responsive. Treatment-free survival at 1 year was 54%. On multivariate analysis, perianal disease was associated with adverse treatment-free survival (hazard ratio 2.34, 95% confidence interval [CI] 1.14-4.83, p = 0.02). One patient died due to infectious complications [cytomegalovirus disease] at Day +56. CONCLUSIONS In this multicentre retrospective analysis of European centres, AHSCT was relatively safe and appeared to be effective in controlling otherwise treatment-resistant Crohn's disease. Further prospective randomised controlled trials against standard of care are warranted.
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Affiliation(s)
- Charlotte K Brierley
- Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, UK,Corresponding author: Dr Charlotte Brierley, MA, MRCP, Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford OX3 7LE, UK.
| | - Cristina Castilla-Llorente
- Unité de transplantation des cellules souches, Département d’Hématologie Gustave Roussy, Villejuif, France
| | - Myriam Labopin
- EBMT Paris Study Office, Department of Haematology, Université Pierre et Marie Curie, Saint Antoine Hospital, Paris, France
| | - Manuela Badoglio
- EBMT Paris Study Office, Department of Haematology, Université Pierre et Marie Curie, Saint Antoine Hospital, Paris, France
| | - Montserrat Rovira
- BMT Unit, Haematology Department, Hospital Clínic of Barcelona, IDIBAPS, Institut Josep Carreras, Barcelona, Spain
| | - Elena Ricart
- Gastroenterology Department, Hospital Clínic of Barcelona, CIBER-EHD, IDIBAPS, Barcelona, Spain
| | - Daan Dierickx
- Department of Haematology, University Hospitals Leuven, Leuven, Belgium
| | - Severine Vermeire
- Department of Gastroenterology, University Hospitals Leuven, Leuven, Belgium
| | - Peter Hasselblatt
- Department of Medicine II, Medical Faculty and University Hospital Freiburg, Freiburg, Germany
| | - Juergen Finke
- Department of Hematology, Oncology and Stem Cell Transplantation, Medical Faculty and University Hospital Freiburg, Freiburg, Germany
| | - Francesco Onida
- Haematology - BMT Centre, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | | | - Jack Satsangi
- Gastro-intestinal Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, UK
| | - Majid Kazmi
- Department of Haematology, Guy’s and St Thomas’ NHS Foundation Trust and King’s College Hospital, London, UK
| | | | - Carsten Schmidt
- Department of Gastroenterology, Medizinische Klinik II, Klinikum Fulda AG, Universitätsmedizin Marburg-Campus, Fulda, Germany
| | - Dominique Farge
- Internal Medicine, Autoimmune and Vascular Diseases Unit, UF 04, AP-HP Hôpital Saint-Louis, Centre de Référence des Maladies auto-immunes systémiques Rares d’Ile-de-France [site constitutif], Filière FAI2R Paris 7 University, France
| | - Simon P L Travis
- Translational Gastroenterology Unit, Oxford University Hospitals, Oxford, UK
| | - Chris J Hawkey
- Nottingham Digestive Diseases Centre, School of Clinical Sciences, Queen’s Medical Centre, Nottingham, UK
| | - John A Snowden
- Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
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Snowden JA, Panés J, Alexander T, Allez M, Ardizzone S, Dierickx D, Finke J, Hasselblatt P, Hawkey C, Kazmi M, Lindsay JO, Onida F, Salas A, Saccardi R, Vermeire S, Rovira M, Ricart E. Autologous Haematopoietic Stem Cell Transplantation (AHSCT) in Severe Crohn's Disease: A Review on Behalf of ECCO and EBMT. J Crohns Colitis 2018; 12:476-488. [PMID: 29325112 DOI: 10.1093/ecco-jcc/jjx184] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2017] [Accepted: 01/04/2018] [Indexed: 02/06/2023]
Abstract
Despite the major recent progress in the treatment of Crohn's disease [CD], there is a subset of patients in whom the disease runs an aggressive course with progressive tissue damage requiring early and repeated surgical management. Increasing evidence supports sustained and profound improvement in gastrointestinal parameters and quality of life following high-dose immunosuppressive therapy and autologous haematopoietic stem cell transplantation [AHSCT] compared to standard therapy in this context. In addition, international transplant registry data reflect the use of AHSCT in CD outside of trials in selected patients. However, AHSCT may be associated with significant treatment-related complications with risk of transplant-related mortality. In a joint initiative, the European Crohn's and Colitis Organisation [ECCO] and the European Society for Blood and Marrow Transplantation [EBMT] have produced a state-of-the-art review of the rationale, evaluation, patient selection, stem cell mobilization and transplant procedures and long-term follow up. Given the unique spectrum of issues, we recommend that AHSCT should only be performed in experienced centres with expertise in both haematological and gastroenterological aspects of the procedure. Where possible, patients should be enrolled on clinical trials and data registered centrally. Future development should be coordinated at both national and international levels.
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Affiliation(s)
- John A Snowden
- Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield, UK
| | - Julián Panés
- Department of Gastroenterology, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Tobias Alexander
- Department of Rheumatology and Clinical Immunology, Charité - University Medicine, Berlin, Germany
| | - Matthieu Allez
- Department of Gastroenterology, Hôpital Saint Louis, APHP, INSERM U1160, Paris Diderot, Sorbonne Paris-Cité University, Paris, France
| | - Sandro Ardizzone
- DIBIC - ASST Fatebenefratelli Sacco - University of Milan, Italy
| | - Daan Dierickx
- Department of Haematology, University Hospitals, Leuven, Belgium
| | - Jürgen Finke
- Department of Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany
| | - Peter Hasselblatt
- Department of Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany
| | - Chris Hawkey
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK
| | - Majid Kazmi
- Department of Haematology, Guys & St Thomas' NHS Foundation Trust, London, UK
| | - James O Lindsay
- The Royal London Hospital, Barts Health NHS Trust, London UK & Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Francesco Onida
- Hematology-BMT Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico - University of Milan, Italy
| | - Azucena Salas
- Department of Gastroenterology, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Riccardo Saccardi
- Department of Haematology, Careggi University Hospital, Firenze, Italy
| | - Severine Vermeire
- Department of Gastroenterology - University Hospitals, Leuven, Belgium
| | - Montserrat Rovira
- BMT Unit, Hematology Department, IDIBAPS, Hospital Clinic. Josep Carreras Leukaemia Research Institute (IJC), Barcelona, Spain
| | - Elena Ricart
- Department of Gastroenterology, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, Spain
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López-García A, Rovira M, Jauregui-Amezaga A, Marín P, Barastegui R, Salas A, Ribas V, Feu F, Elizalde JI, Fernández-Avilés F, Martínez C, Gutiérrez G, Rosiñol L, Carreras E, Urbano A, Lozano M, Cid J, Suárez-Lledó M, Masamunt MC, Comas D, Giner A, Gallego M, Alfaro I, Ordás I, Panés J, Ricart E. Autologous Haematopoietic Stem Cell Transplantation for Refractory Crohn's Disease: Efficacy in a Single-Centre Cohort. J Crohns Colitis 2017; 11:1161-1168. [PMID: 28419282 DOI: 10.1093/ecco-jcc/jjx054] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Accepted: 04/12/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Haematopoietic stem cell transplantation [HSCT] is considered a therapeutic option for patients with severe Crohn's disease [CD] unresponsive to currently available therapies. METHODS Autologous HSCT was considered for CD patients with active disease, unresponsive or intolerant to approved medications and unsuitable for surgery. After HSCT, patients were closely followed up every 6 weeks during the first 2 years and every 6 months thereafter up to 5 years. Colonoscopy and/or magnetic resonance imaging were performed at Months 6, 12, 24, and 48 after HSCT. RESULTS From December 1, 2007 to December 31, 2015, 37 CD patients were assessed for HSCT. Of these, 35 patients [13 within the ASTIC trial] underwent mobilisation. Six patients did not complete the transplant for various reasons and 29 patients were finally transplanted. Patients were followed up during a median of 12 months [6-60]. At 6 months, 70% of patients achieved drug-free clinical remission (Crohn's Disease Index of Severity [CDAI] < 150). The proportion of patients in drug-free remission (CDAI < 150, Simple Endoscopic activity Score [SES]-CD < 7] was 61% at 1 year, 52% at 2 years, 47% at 3 years, 39% at 4 years, and 15% at 5 years. Patients who relapsed were re-treated and 80% regained clinical remission. Six out of the 29 [21%] required surgery. One patient died due to systemic cytomegalovirus infection 2 months after transplant. CONCLUSIONS HSCT is a salvage therapy for patients with extensive and refractory CD. Although relapse occurs in a majority of patients within 5 years after transplant, drug responsiveness is regained and clinical remission achieved in 80% of cases.
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Affiliation(s)
- Alicia López-García
- Gastroenterology Department, Hospital Clínic de Barcelona, CIBEREHD, Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Montserrat Rovira
- Hematology Department-HSCT Unit, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Aranzazu Jauregui-Amezaga
- Gastroenterology Department, Hospital Clínic de Barcelona, CIBEREHD, Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Pedro Marín
- Hemotherapy and Hemostasis Department, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Rebeca Barastegui
- Gastroenterology Department, Hospital Clínic de Barcelona, CIBEREHD, Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Azucena Salas
- Gastroenterology Department, Hospital Clínic de Barcelona, CIBEREHD, Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Vicent Ribas
- EURECAT, Centre Tecnològic de Catalunya, Barcelona, Spain
| | - Faust Feu
- Gastroenterology Department, Hospital Clínic de Barcelona, CIBEREHD, Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - J Ignasi Elizalde
- Gastroenterology Department, Hospital Clínic de Barcelona, CIBEREHD, Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | | | - Carmen Martínez
- Hematology Department-HSCT Unit, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Gonzalo Gutiérrez
- Hematology Department-HSCT Unit, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Laura Rosiñol
- Hematology Department-HSCT Unit, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Enric Carreras
- Hematology Department-HSCT Unit, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Alvaro Urbano
- Hematology Department-HSCT Unit, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Miguel Lozano
- Hemotherapy and Hemostasis Department, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Joan Cid
- Hemotherapy and Hemostasis Department, Hospital Clínic de Barcelona, Barcelona, Spain
| | - María Suárez-Lledó
- Hematology Department-HSCT Unit, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Maria Carme Masamunt
- Gastroenterology Department, Hospital Clínic de Barcelona, CIBEREHD, Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Dolors Comas
- Gastroenterology Department, Hospital Clínic de Barcelona, CIBEREHD, Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Angel Giner
- Gastroenterology Department, Hospital Clínic de Barcelona, CIBEREHD, Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Marta Gallego
- Gastroenterology Department, Hospital Clínic de Barcelona, CIBEREHD, Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Ignacio Alfaro
- Gastroenterology Department, Hospital Clínic de Barcelona, CIBEREHD, Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Ingrid Ordás
- Gastroenterology Department, Hospital Clínic de Barcelona, CIBEREHD, Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Julian Panés
- Gastroenterology Department, Hospital Clínic de Barcelona, CIBEREHD, Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Elena Ricart
- Gastroenterology Department, Hospital Clínic de Barcelona, CIBEREHD, Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
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Qiu Y, Li MY, Feng T, Feng R, Mao R, Chen BL, He Y, Zeng ZR, Zhang SH, Chen MH. Systematic review with meta-analysis: the efficacy and safety of stem cell therapy for Crohn's disease. Stem Cell Res Ther 2017; 8:136. [PMID: 28583202 PMCID: PMC5460506 DOI: 10.1186/s13287-017-0570-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background and aims Stem cell therapy (SCT) for the treatment of Crohn’s disease (CD) is still in its infancy, and whether SCT is associated with improved outcomes is unclear. We performed a meta-analysis to evaluate the efficacy and safety of patients receiving SCT. Methods Electronic databases were searched for studies that reported the use of stem cells for the treatment of patients with CD. Raw data from included studies were pooled for effect estimates. Subgroup analyses were performed for exploration of heterogeneity regarding all outcomes. Results We analyzed 21 studies comprising 514 patients with active CD. A random-effects meta-analysis of studies of SCT as systemic infusion showed 56% (95% confidence interval (CI) 33–76, n = 150) of patients achieved clinical response. Similarly, random-effects pooled rates of clinical or endoscopic remission were 46% (95% CI 25–69, n = 116) and 15% (95% CI 0–50, n = 48), respectively. A random-effects meta-analysis of all perianal CD studies showed that 57% (95% CI 44–69%, n = 251) of patients had healed fistula with SCT, with an odds ratio of 3.83 (95% CI 1.06–13.86, n = 121, P = 0.04) versus control. The pooled rate of clinical recurrence was high at 16% (95% CI 4–34, n = 101) with follow-up >12 months. The pooled rates of severe adverse events (SAEs) and SAEs related to SCT were 12% (95% CI 6–23, n = 378) and 8% (95% CI 3–18, n = 378), respectively. The Egger test suggests no publication bias existed for fistula healing (P = 0.36), but did for clinical response (P = 0.003). Conclusions SCT seems potentially effective and may serve as an alternative treatment for refractory active CD. Toxicity will remain the most significant barrier to systemic SCT in patients with CD. Electronic supplementary material The online version of this article (doi:10.1186/s13287-017-0570-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yun Qiu
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Man-Ying Li
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Ting Feng
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Rui Feng
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Ren Mao
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Bai-Li Chen
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Yao He
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Zhi-Rong Zeng
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Sheng-Hong Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China.
| | - Min-Hu Chen
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China.
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Qiu X, Feng JR, Chen LP, Liu S, Zhang M, Zhou Z, Liu J, Zhao Q. Efficacy and safety of autologous hematopoietic stem cell therapy for refractory Crohn's disease: A systematic review and meta-analysis. Medicine (Baltimore) 2017; 96:e7381. [PMID: 28658168 PMCID: PMC5500090 DOI: 10.1097/md.0000000000007381] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Autologous hematopoietic stem cell transplantation (HSCT) has been proposed for patients with refractory Crohn's disease (CD), but it is associated with mortality and adverse events; the balance between risks and benefits becomes significantly important in the therapy. The aim of the study was to assess the efficacy and safety of autologous HSCT therapy for refractory CD. METHODS We conducted a comprehensive search of PubMed, Embase, the Cochrane library, and Web of Science from inception to February 2017. The pooled estimate rates for efficacy and safety of refractory CD was performed by meta-analysis and reported according to the standard Cochrane guidelines and the PRISMA statement. RESULTS Four prospective uncontrolled cohort studies, 4 prospective case series, and 1 randomized controlled trial (RCT) were included. Autologous HSCT had a high rate of clinical and endoscopic remission in refractory CD [79.4%, 95% confidence interval (95% CI): 0.550-0.924; 81.9%, 95% CI: 0.603-0.931, respectively]. In the case of safety, it had a relatively high incidence rate of transplant-related mortality (6.4%, 95% CI: 0.028-0.140). A significant association was observed between autologous HSCT and the incidence of febrile neutropenia (83.2%, 95% CI: 0.632-0.934). About 18.5% (95% CI: 0.061-0.442) of patients with refractory CD reached clinical remission at mobilization phase. Besides, 82.1% (95% CI: 0.692-0.903) and 54.1% (95% CI: 0.261-0.797) patients with refractory CD could achieve immunosuppressive-free and steroid-free remission for at least 12 months after the therapy. CONCLUSION Autologous HSCT could be a complicated treatment with relatively high mortality and significantly high efficacy for refractory CD, which should be used with caution. However, more RCTs of larger samples using refined and standardized protocols and longer period of follow-up time are needed to further assess the outcomes of autologous HSCT therapy.
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Affiliation(s)
- Xiao Qiu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University
- Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan, China
| | - Jue-Rong Feng
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University
- Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan, China
| | - Li-Ping Chen
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University
- Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan, China
| | - Shi Liu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University
- Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan, China
| | - Meng Zhang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University
- Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan, China
| | - Zhou Zhou
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University
- Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan, China
| | - Jing Liu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University
- Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan, China
| | - Qiu Zhao
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University
- Hubei Clinical Center & Key Laboratory of Intestinal & Colorectal Diseases, Wuhan, China
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Zeher M, Papp G, Nakken B, Szodoray P. Hematopoietic stem cell transplantation in autoimmune disorders: From immune-regulatory processes to clinical implications. Autoimmun Rev 2017; 16:817-825. [PMID: 28572052 DOI: 10.1016/j.autrev.2017.05.020] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 04/28/2017] [Indexed: 12/29/2022]
Abstract
Autoimmune diseases are characterized by the development of autoreactive T- and B-cells targeting self-antigens, which eventually can result in chronic and persistent organ damage. The autologous hematopoietic stem cell transplantation (AHSCT) opened new avenues in the treatment of patients with severe, treatment-resistant autoimmune diseases. This paper reviews the immune-regulatory mechanisms behind AHSCT, and also summarizes the experiences of clinical practice related to the therapy in organ-specific and systemic autoimmune diseases. It seems that the intricate interplay of various immune competent cells with regulatory capacity control in a synergistic manner the repopulated immune system after AHSCT, which potentially leads to a significant clinical improvement in certain autoimmune diseases. However, the widespread use of AHSCT was intrinsically limited, due to the serious side-effects of conditioning treatment and relatively high treatment-related mortality; moreover, the development of new effective and safe therapeutic approaches and the dawn of biological agents further limited its indications in the last decade. Nevertheless, with an appropriate patient selection and increased experience of transplant centres, the risks can be minimized, and AHSCT remained still a reasonable choice in multiple sclerosis and systemic sclerosis when the conventional therapy failed and further progression of disease is inevitable.
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Affiliation(s)
- Margit Zeher
- Division of Clinical Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
| | - Gábor Papp
- Division of Clinical Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Britt Nakken
- Centre for Immune Regulation, Department of Immunology, University of Oslo, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Peter Szodoray
- Centre for Immune Regulation, Department of Immunology, University of Oslo, Oslo University Hospital, Rikshospitalet, Oslo, Norway
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20
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Lindsay JO, Allez M, Clark M, Labopin M, Ricart E, Rogler G, Rovira M, Satsangi J, Farge D, Hawkey CJ. Autologous stem-cell transplantation in treatment-refractory Crohn's disease: an analysis of pooled data from the ASTIC trial. Lancet Gastroenterol Hepatol 2017; 2:399-406. [PMID: 28497755 DOI: 10.1016/s2468-1253(17)30056-0] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Revised: 02/03/2017] [Accepted: 02/08/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND The randomised controlled ASTIC trial showed no benefit of mobilisation and autologous haematopoietic stem-cell transplantation (HSCT) compared with mobilisation followed by conventional therapy using a stringent primary endpoint (steroid-free clinical remission for 3 months with no endoscopic or radiological evidence of intestinal inflammation) in patients with treatment-refractory Crohn's disease. We now assess HSCT in patients enrolled in the ASTIC trial using endpoints that are traditional for clinical trials in Crohn's disease, and identify factors that predict benefit or harm. METHODS Patients who underwent mobilisation and were randomly assigned to conventional therapy in the ASTIC trial were offered HSCT at 1 year and underwent complete assessment for a further year. We report analyses of the combined cohort of patients who underwent HSCT at any time during the ASTIC trial programme. The primary outcome for this analysis was 3-month steroid-free clinical remission at 1 year after HSCT (Crohn's Disease Activity Index [CDAI] <150). We also examined the degree of endoscopic healing at 1 year. Multivariate analysis was performed to identify factors associated with achieving the primary endpoint by using logistic regression, and factors associated with experiencing a serious adverse event using Poisson regression. Participants were not masked to treatment, but the adjudication panel that reviewed radiology and endoscopy was masked to allocation and visits. All patients who underwent HSCT and had data available at baseline and 1-year follow-up were included in the primary and safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00297193. FINDINGS Between June 28, 2007, and Sept 1, 2011, 45 patients were enrolled in the ASTIC trial from 11 European transplant units. 23 patients were randomly assigned to immediate HSCT, and 22 patients were assigned to mobilisation followed by conventional care. After completion of the ASTIC trial, 17 patients from the conventional care group received HSCT. In the combined cohort, data were available for 40 patients at baseline and 38 patients at 1 year after HSCT (one patient died, one withdrew). At 1 year after HSCT, 3-month steroid-free clinical remission was seen in 13 (38%, 95% CI 22-55) of 34 patients with available data for the whole year. Complete endoscopic healting was noted in 19 (50%, 34-66) of 38 patients. On multivariate analyses, factors associated with the primary outcome were short disease duration (odds ratio [OR] 0·64, 95% CI 0·41-0·997 per year; p=0·048) and low baseline CDAI (0·82, 0·74-0·98 per 10 units; p=0·031). 76 serious adverse events occurred in 23 of 40 patients with available data. The most common serious adverse event was infection, most of which were treatment related. Smoking and perianal disease at baseline were independent factors associated with the number of serious adverse events (OR 3·07 [95% CI 1·75-5·38; p=0·0001] for smoking and 3·97 [2·17-7·25; p<0·0001] for perianal disease) on multivariate analysis. INTERPRETATION When assessed using endpoints traditional for clinical trials of conventional therapy in Crohn's disease, HSCT resulted in clinical and endoscopic benefit, although it was associated with a high burden of adverse events. The prognostic factors identified could allow the therapy to be targeted to patients most likely to benefit and not experience serious adverse events. FUNDING Broad Medical Research Program, National Institute for Health Research Senior Investigator Award, The University of Nottingham Medical School Dean's Fund, and The Nottingham University Hospitals NHS Trust Research and Development Fund.
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Affiliation(s)
- James O Lindsay
- Barts and the London School of Medicine and Dentistry, London, UK.
| | - Mathieu Allez
- Department of Gastroenterology, Hôpital Saint Louis, APHP, INSERM UMRS 1160, Paris Diderot, Sorbonne Paris-Cité Unversity, Paris, France
| | - Miranda Clark
- Centre for Digestive Diseases, Queens Medical Centre, Nottingham, UK
| | - Myriam Labopin
- Department of Haematology, Saint Antoine Hospital, AP-HP, Université Pierre et Marie Curie, EBMT Paris Study Office/CEREST-TC, Paris, France
| | - Elenor Ricart
- Department of Gastroenterology, Hospital Clinic, CIBER-EHD, IDIBAPS, Barcelona, Spain
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital, Zurich, Switzerland
| | | | - Jack Satsangi
- Department of Gastroenterology, Western General Hospital, University of Edinburgh, Edinburgh, UK
| | - Dominique Farge
- Unité Clinique de Médecine Interne, Maladies Auto-immunes et Pathologie Vasculaire, UF 04, Hôpital Saint-Louis, AP-HP Assistance Publique des Hôpitaux de Paris, INSERM UMRS 1160, Paris Denis-Diderot Université, Paris, France
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21
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DiNicola CA, Zand A, Hommes DW. Autologous hematopoietic stem cells for refractory Crohn's disease. Expert Opin Biol Ther 2017; 17:555-564. [PMID: 28326848 DOI: 10.1080/14712598.2017.1305355] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Autologous hematopoietic stem cells are gaining ground as an effective and safe treatment for treating severe refractory Crohn's disease (CD). Autologous hematopoietic stem cell therapy (AHSCT) induces resetting of the immune system by de novo regeneration of T-cell repertoire and repopulation of epithelial cells by bone-marrow derived cells to help patients achieve clinical and endoscopic remission. Areas covered: Herein, the authors discuss the use of AHSCT in treating patients with CD. Improvements in disease activity have been seen in patients with severe autoimmune disease and patients with severe CD who underwent AHSCT for a concomitant malignant hematological disease. Clinical and endoscopic remission has been achieved in patients treated with AHSCT for CD. The only randomized trial published to date, the ASTIC Trial, did not support further use of AHSCT to treat CD. Yet, critics of this trial have deemed AHSCT as a promising treatment for severe refractory CD. Expert opinion: Even with the promising evidence presented for HSCT for refractory CD, protocols need to be refined through the collaboration of GI and hemato-oncology professionals. The goal is to incorporate safe AHSCT and restore tolerance by delivering an effective immune 'cease fire' as a treatment option for severe refractory CD.
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Affiliation(s)
- C A DiNicola
- a Department of Medicine , UCLA Center for Inflammatory Bowel Diseases , Los Angeles , CA , USA.,b Vatche & Tamar Manoukian Divison of Digestive Diseases , University of California , Los Angeles , CA , USA
| | - A Zand
- a Department of Medicine , UCLA Center for Inflammatory Bowel Diseases , Los Angeles , CA , USA.,b Vatche & Tamar Manoukian Divison of Digestive Diseases , University of California , Los Angeles , CA , USA
| | - D W Hommes
- a Department of Medicine , UCLA Center for Inflammatory Bowel Diseases , Los Angeles , CA , USA.,b Vatche & Tamar Manoukian Divison of Digestive Diseases , University of California , Los Angeles , CA , USA
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Hawkey CJ, Hommes DW. Is Stem Cell Therapy Ready for Prime Time in Treatment of Inflammatory Bowel Diseases? Gastroenterology 2017; 152:389-397.e2. [PMID: 27845055 DOI: 10.1053/j.gastro.2016.11.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Revised: 10/20/2016] [Accepted: 11/08/2016] [Indexed: 02/07/2023]
Abstract
Autologous hematopoietic stem cell transplantation (HSCT) and mesenchymal stromal cell therapy have been proposed for patients with refractory Crohn's disease (CD) and fistulizing CD, respectively. Will these highly advanced techniques be available only for select patients, at specialized centers, or is further clinical development justified, with the aim of offering widespread, more definitive therapeutic options for often very difficult to treat disease? Patients with CD who are eligible for HSCT have typically been failed by most approved therapies, have undergone multiple surgeries, and have coped with years of disease activity and poor quality of life. The objective of HSCT is to immediately shut down the immune response and allow the transplanted stem cells to develop into self-tolerant lymphocytes. For patients with fistulizing CD, mesenchymal stromal cell therapy deposits MSCs locally, into fistulizing tracts, to down-regulate the local immune response and induce wound healing. Recent trials have produced promising results for HSCT and mesenchymal stromal cell therapy as alternatives to systemic therapies and antibiotics for patients with inflammatory bowel diseases, but are these immunotherapies ready for prime time?
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Affiliation(s)
- Christopher J Hawkey
- Nottingham Digestive Diseases Center, University of Nottingham, Nottingham, United Kingdom
| | - Daniel W Hommes
- Center for Inflammatory Bowel Diseases, University of California Los Angeles, Los Angeles, California.
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Suppression of colitis by adoptive transfer of helminth antigen-treated dendritic cells requires interleukin-4 receptor-α signaling. Sci Rep 2017; 7:40631. [PMID: 28094779 PMCID: PMC5240550 DOI: 10.1038/srep40631] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Accepted: 12/08/2016] [Indexed: 12/18/2022] Open
Abstract
Infection with helminth parasites has been explored as a treatment for autoimmune and inflammatory diseases. As helminth antigens have potent immunomodulation properties capable of inducing regulatory programs in a variety of cell types, transferring cells treated with helminth antigens represents a novel extension to helminth therapy. Previous work determined that transfer of bone marrow-derived dendritic cells (DC) pulsed with a crude extract of the tapeworm Hymenolepis diminuta (HD) can suppress colitis in recipient mice. The present study explored the mechanism of disease suppression and the importance of interleukin (IL)-4 signaling. Transfer of HD-DCs suppressed dinitrobenzene sulfonic acid (DNBS)-induced colitis through activation of recipient IL-4 receptor-α. The transferred HD-DCs required IL-4Rα and the capacity to secrete IL-10 to drive IL-4 and IL-10 production and to suppress colitis in recipient mice. Treatment of DCs with IL-4 evokes an alternatively activated phenotype, but adoptive transfer of these cells did not affect the outcome of colitis. Collectively, these studies demonstrate the complexity between IL-4 and IL-10 in donor cells and recipient, and the requirement for parasite- and host-derived factors in this novel form of cell therapy. Thus IL-4Rα signaling is revealed as a pathway that could be exploited for helminth antigen cell-based therapy.
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Rebeiro P, Moore J. The role of autologous haemopoietic stem cell transplantation in the treatment of autoimmune disorders. Intern Med J 2016; 46:17-28. [PMID: 26524106 DOI: 10.1111/imj.12944] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Revised: 07/14/2015] [Accepted: 10/19/2015] [Indexed: 12/29/2022]
Abstract
Autologous haemopoietic stem cell transplantation (HSCT) has been used for over 30 years for malignant haematological diseases, such as myeloma and lymphoma, with considerable success. More recently this procedure has been adopted as a form of high dose immunosuppression in selected patients with autoimmune diseases that are resistant to conventional therapies. Animal models have previously outlined the rationale and validity of HSCT in patients with these non-malignant, but in many cases, life-threatening conditions. Recent data have that deletion of putative autoreactive immune clones with reconstitution of a thymic driven, tolerant immune system occurs in HSCT for auto-immune patients. Two randomised control trials have confirmed that HSCT is superior to monthly cyclophosphamide in systemic sclerosis with a highly significant disease free and overall survival benefit demonstrated in the Autologous Stem cell Transplantation International Scleroderma trial. Over 2000 patients worldwide with autoimmune conditions have been treated with HSCT - the commonest indications being multiple sclerosis (MS) and systemic sclerosis. Encouraging relapse free survival of 70-80% at 4 years, in heavily pre-treated MS patients, has been demonstrated in Phase II trials. A Phase III trial in MS patients who have failed interferon is currently accruing patients. Future challenges include improvements in safety of HSCT, particularly in cardiac assessment of systemic sclerosis patients, cost-benefit analyses of HSCT compared to standard therapy and establishment of centres of excellence to continue to enhance the safety and benefit of this exciting new therapy.
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Affiliation(s)
- P Rebeiro
- Haematology Department, St Vincents Hospital, Sydney, New South Wales, Australia
| | - J Moore
- Haematology Department, St Vincents Hospital, Sydney, New South Wales, Australia
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Abstract
By reputation, the parasite is a pariah, an unwelcome guest. Infection with helminth parasites evokes stereotypic immune responses in humans and mice that are dominated by T helper (Th)-2 responses; thus, a hypothesis arises that infection with helminths would limit immunopathology in concomitant inflammatory disease. Although infection with some species of helminths can cause devastating disease and affect the course of microbial infections, analyses of rodent models of inflammatory disease reveal that infection with helminth parasites, or treatment with helminth extracts, can limit the severity of autoinflammatory disease, including colitis. Intriguing, but fewer, studies show that adoptive transfer of myeloid immune cells treated with helminth products/extracts in vitro can suppress inflammation. Herein, 3 facets of helminth therapy are reviewed and critiqued: treatment with viable ova or larvae, treatment with crude extracts of the worm or purified molecules, and cellular immunotherapy. The beneficial effect of helminth therapy often converges on the mobilization of IL-10 and regulatory/alternatively activated macrophages, while there are reports on transforming growth factor (TGF)-β, regulatory T cells and dendritic cells, and recent data suggest that helminth-evoked changes in the microbiota should be considered when defining anticolitic mechanisms. We speculate that if the data from animal models translate to humans, noting the heterogeneity therein, then the choice between use of viable helminth ova, helminth extracts/molecules or antigen-pulsed immune cells could be matched to disease management in defined cohorts of patients with inflammatory bowel disease.
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26
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Duran NE, Hommes DW. Stem cell-based therapies in inflammatory bowel disease: promises and pitfalls. Therap Adv Gastroenterol 2016; 9:533-47. [PMID: 27366222 PMCID: PMC4913333 DOI: 10.1177/1756283x16642190] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic, often relapsing, condition that deeply impacts the quality of life for many patients. Although there have been significant advances in medical treatments, a large proportion of patients become refractory to available therapeutic options. Stem-cell therapy through hematopoietic stem cells (HSCs) or mesenchymal stem (stromal) cells (MSCs) is a promising therapeutic option for severe refractory cases especially when surgery is not feasible. In HSC transplantation, the objective is to destroy the 'autoreactive' immune cells responsible for disease chronicity, and to re-establish gut tolerance to gut microbes. In perianal Crohn's disease (CD), the objective is to deposit MSCs locally in fistulizing tracts to down-regulate the local immune response and induce wound healing. Results from upcoming and ongoing clinical trials will set the path of these novel therapeutic options that have the capability to successfully treat severe refractory Crohn's patients.
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Affiliation(s)
| | - Daniel W. Hommes
- Department of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
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27
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Kelsey PJ, Oliveira MC, Badoglio M, Sharrack B, Farge D, Snowden JA. Haematopoietic stem cell transplantation in autoimmune diseases: From basic science to clinical practice. Curr Res Transl Med 2016; 64:71-82. [PMID: 27316390 DOI: 10.1016/j.retram.2016.03.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 03/31/2016] [Indexed: 12/20/2022]
Abstract
Based on animal studies and serendipitous clinical cases, haematopoietic stem cell transplantation (HSCT) has been used since 1995 as a specific treatment for patients with severe treatment-resistant autoimmune disease (ADs). Despite other clinical developments for autoimmune diseases, including biological therapies, there has been an ongoing requirement for HSCT in some diseases and several thousand procedures have been registered in databases for a wide variety of diseases, predominantly for treatment with autologous HSCT. Currently, the main indications are multiple sclerosis, systemic sclerosis and Crohn's disease, which are supported by large series and randomised controlled trials (RCTs), whereas retrospective registry analyses support benefit in a range of rarer indications. Research into mechanisms of action has provided insight into how tolerance may be achieved with an intensive one-off treatment. In addition to the profound anti-inflammatory and immunosuppressive effects provided by the cytotoxic regimen, long-term responses in some diseases may be explained by 'resetting' the immune system through thymic reprocessing and generation of increased T-regulatory cell activity. This review aims to summarise the gradual evolution of HSCT in severe autoimmune diseases over the last 20 years, focussing on the recent publication of clinical and scientific studies, as well as evidence-based guidelines and recommendations.
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Affiliation(s)
- P J Kelsey
- Departments of Haematology and Neurology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Glossop Road, Sheffield, UK.
| | - M-C Oliveira
- Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | | | - B Sharrack
- Departments of Haematology and Neurology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Glossop Road, Sheffield, UK
| | - D Farge
- St. Louis hospital, Internal Medicine and Vascular Diseases Unit, Paris, France; INSERM 1160 Unit, Paris 7 Diderot University, Sorbonne Paris Cite 1, Paris, France
| | - J A Snowden
- Departments of Haematology and Neurology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Glossop Road, Sheffield, UK
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28
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Ciccocioppo R, Cangemi GC, Kruzliak P, Corazza GR. Concise Review: Cellular Therapies: The Potential to Regenerate and Restore Tolerance in Immune-Mediated Intestinal Diseases. Stem Cells 2016; 34:1474-86. [PMID: 27016400 DOI: 10.1002/stem.2367] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Revised: 03/01/2016] [Accepted: 03/10/2016] [Indexed: 12/18/2022]
Abstract
Chronic inflammatory enteropathies, including celiac disease, Crohn's disease, and ulcerative colitis, are lifelong disabling conditions whose cure is still an unmet need, despite the great strides made in understanding their complex pathogenesis. The advent of cellular therapies, mainly based on the use of stem cells, represents a great step forward thanks to their multitarget strategy. Both hematopoietic stem cells (HSC) and mesenchymal stem/stromal cells (MSC) have been employed in the treatment of refractory cases with promising results. The lack of immunogenicity makes MSC more suitable for therapeutic purposes as their infusion may be performed across histocompatibility locus antigen barriers without risk of rejection. The best outcome has been obtained when treating fistulizing Crohn's disease with local injections of MSC. In addition, both HSC and MSC proved successful in promoting regeneration of intestinal mucosa, and favoring the expansion of a T-cell regulatory subset. By virtue of the ability to favor mucosal homeostasis, this last cell population has been exploited in clinical trials, with inconsistent results. Finally, the recent identification of the epithelial stem cell marker has opened up the possibility of tissue engineering, with an array of potential applications for intestinal diseases. However, the underlying mechanisms of action of these interconnected therapeutic strategies are still poorly understood. It is conceivable that over the next few years their role will become clearer as the biological interactions with injured tissues and the hierarchy by which they deliver their action are unraveled through a continuous moving from bench to bedside and vice versa. Stem Cells 2016;34:1474-1486.
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Affiliation(s)
- Rachele Ciccocioppo
- Clinica Medica I, Department of Internal Medicine Fondazione IRCCS Policlinico San Matteo, Università degli Studi di Pavia, Italy
| | - Giuseppina Cristina Cangemi
- Clinica Medica I, Department of Internal Medicine Fondazione IRCCS Policlinico San Matteo, Università degli Studi di Pavia, Italy
| | - Peter Kruzliak
- Laboratory of Structural Biology and Proteomics, Central Laboratories, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic
| | - Gino Roberto Corazza
- Clinica Medica I, Department of Internal Medicine Fondazione IRCCS Policlinico San Matteo, Università degli Studi di Pavia, Italy
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29
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Leitner GC, Vogelsang H. Pharmacological- and non-pharmacological therapeutic approaches in inflammatory bowel disease in adults. World J Gastrointest Pharmacol Ther 2016; 7:5-20. [PMID: 26855808 PMCID: PMC4734954 DOI: 10.4292/wjgpt.v7.i1.5] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 12/14/2015] [Accepted: 01/08/2016] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) are a group of chronic inflammatory conditions mainly of the colon and small intestine. Crohn's disease (CD) and ulcerative colitis (UC) are the most frequent types of IBD. IBD is a complex disease which arises as a result of the interaction of environmental, genetic and immunological factors. It is increasingly thought that alterations of immunological reactions of the patients to their own enterable bacteria (microfilm) may contribute to inflammation. It is characterized by mucosal and sub mucosal inflammation, perpetuated by infiltration of activated leukocytes. CD may affect the whole gastrointestinal tract while UC only attacks the large intestine. The therapeutic goal is to achieve a steroid-free long lasting remission in both entities. UC has the possibility to be cured by a total colectomy, while CD never can be cured by any operation. A lifelong intake of drugs is mostly necessary and essential. Medical treatment of IBD has to be individualized to each patient and usually starts with anti-inflammatory drugs. The choice what kind of drugs and what route administered (oral, rectal, intravenous) depends on factors including the type, the localization, and severity of the patient's disease. IBD may require immune-suppression to control symptoms such as prednisolone, thiopurines, calcineurin or sometimes folic acid inhibitors or biologics like TNF-α inhibitors or anti-integrin antibodies. For both types of disease (CD, UC) the same drugs are available but they differ in their preference in efficacy between CD and UC as 5-aminosalicylic acid for UC or budesonide for ileocecal CD. As therapeutic alternative the main mediators of the disease, namely the activated pro-inflammatory cytokine producing leukocytes can be selectively removed via two apheresis systems (Adacolumn and Cellsorba) in steroid-refractory or dependent cases. Extracorporeal photopheresis results in an increase of regulatory B cells, regulatory CD8(+) T cells and T-regs Type 1. Both types of apheresis were able to induce clinical remission and mucosal healing accompanied by tapering of steroids.
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Shah SC, Colombel JF, Sands BE, Narula N. Systematic review with meta-analysis: mucosal healing is associated with improved long-term outcomes in Crohn's disease. Aliment Pharmacol Ther 2016; 43:317-33. [PMID: 26607562 DOI: 10.1111/apt.13475] [Citation(s) in RCA: 267] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Revised: 10/10/2015] [Accepted: 10/22/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND Clinical manifestations of Crohn's disease (CD) do not reliably correlate with endoscopic activity. While treating to achieve clinical remission (CR) has neither proven to improve CD outcomes nor alter the natural disease course, it is unclear whether targeting objective measures like mucosal healing (MH) is associated with improved long-term outcomes. AIM To perform a systematic review and meta-analysis comparing long-term outcomes in active CD patients who achieve MH compared to those who do not. METHODS We performed a systematic literature search to identify studies with prospective cohorts of active CD patients that included outcomes of patients who achieved MH at first endoscopic assessment (MH1) compared to those who did not. The primary outcome was long-term (≥50 weeks) CR. Secondary outcomes included CD-related surgery-free rate, hospitalisation-free rate and long-term MH rate. Pooled odds ratio (OR) and 95% confidence intervals (CI) were calculated. RESULTS Twelve studies with 673 patients met inclusion criteria. Patients achieving MH1 had a pooled OR of 2.80 (95%CI, 1.91-4.10) for achieving long-term CR, 2.22 (95%CI, 0.86-5.69) for CD-related surgery-free rate, and 14.30 (95%CI, 5.57-36.74) for long-term MH. Sensitivity analyses suggested no difference in outcomes if MH1 was achieved on biologics vs. non-biologics. No significant publication bias or heterogeneity was detected. CONCLUSIONS Achieving MH1 is associated with increased rates of long-term clinical remission, and maintenance of mucosal healing in active Crohn's disease and may therefore be a reasonable therapeutic target.
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Affiliation(s)
- S C Shah
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - J-F Colombel
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - B E Sands
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - N Narula
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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31
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Flores AI, Gómez-Gómez GJ, Masedo-González &A, Martínez-Montiel MP. Stem cell therapy in inflammatory bowel disease: A promising therapeutic strategy? World J Stem Cells 2015; 7:343-351. [PMID: 25815119 PMCID: PMC4369491 DOI: 10.4252/wjsc.v7.i2.343] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 09/24/2014] [Accepted: 11/10/2014] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases are inflammatory, chronic and progressive diseases of the intestinal tract for which no curative treatment is available. Research in other fields with stem cells of different sources and with immunoregulatory cells (regulatory T-lymphocytes and dendritic T-cells) opens up new expectations for their use in these diseases. The goal for stem cell-based therapy is to provide a permanent cure. To achieve this, it will be necessary to obtain a cellular product, original or genetically modified, that has a high migration capacity and homes into the intestine, has high survival after transplantation, regulates the immune reaction while not being visible to the patient’s immune system, and repairs the injured tissue.
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32
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Abstract
Inflammatory bowel disease (IBD) could be curable by "immune rest" and correction of the genetic predisposition inherent in allogeneic hematopoietic stem cell transplantation. However, balancing risks against benefits remains challenging. The application of mesenchymal stem cells (MSCs) serving as a site-regulated "drugstore" is a recent concept, which suggests the possibility of an alternative treatment for many intractable diseases such as IBD. Depending on the required function of MSC, such as a cell provider, immune moderator, and/or trophic resource, MSC therapy should be optimized to maximize its therapeutic benefit. Therapeutic effects do not always require full engraftment of MSCs. Therefore, optimization of pleiotropic gut trophic factors produced by MSCs, which favoring not only regulating immune responses but also promoting tissue repair, must directly enhance new drug discoveries for treatment of IBD. Stem cell biology holds great promise for a new era of cell-based therapy, sparking considerable interest among scientists, clinicians, and patients. However, the translational arm of stem cell science remains in a relatively primitive state. Although several clinical studies using MSCs have been initiated, early results suggest several inherent problems. In each study, optimization of MSC therapy appears to be the most urgent problem, and can be resolved only by scientifically unveiling the mechanisms of therapeutic action. In the present review, the authors outline how such information would facilitate the critical steps in the paradigm shift from basic research on stem cell biology to clinical practice of regenerative medicine for conquering IBD in the near future.
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33
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Ruiz MA, Kaiser Junior RL, Gouvêa Faria MA, de Quadros LG. Remission of refractory Crohn's disease after autologous hematopoietic stem cell transplantation. Rev Bras Hematol Hemoter 2015; 37:136-9. [PMID: 25818827 PMCID: PMC4382571 DOI: 10.1016/j.bjhh.2015.01.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Accepted: 10/27/2014] [Indexed: 12/11/2022] Open
Affiliation(s)
- Milton Artur Ruiz
- Associação Portuguesa de Beneficência, São José do Rio Preto, SP, Brazil.
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34
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Levesque BG, Sandborn WJ, Ruel J, Feagan BG, Sands BE, Colombel JF. Converging goals of treatment of inflammatory bowel disease from clinical trials and practice. Gastroenterology 2015; 148:37-51.e1. [PMID: 25127678 DOI: 10.1053/j.gastro.2014.08.003] [Citation(s) in RCA: 160] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2014] [Revised: 08/02/2014] [Accepted: 08/05/2014] [Indexed: 12/21/2022]
Abstract
It is important to have clear goals for treating inflammatory bowel disease in clinical practice and in research. Conventional end points for trials in ulcerative colitis and Crohn's disease have been based on composite indices, such as the Mayo Clinic Score and the Crohn's Disease Activity Index; these indices incorporate symptoms, signs, and findings from laboratory tests and sometimes endoscopic assessments. Although definitions of clinical response and remission have been based on these indices for regulatory purposes, they are difficult to apply to practice because they are complex and not intuitive to clinicians. This has caused a disconnect between clinical trials and practice. Recently, the use of composite indices in trials has been reevaluated in Food and Drug Administration-sponsored Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics workshops due to concerns about the validity of the indices. Alternative measures of outcome and definitions of response are being developed. Patient-reported outcomes are psychometric instruments created and defined by patients to quantify symptoms. A combination of end points, comprising patient-reported outcomes and objective evaluation of inflammation by endoscopy, offers a clinically meaningful and scientifically valid alternative to existing composite indices. Unlike composite indices, response definitions based on endoscopy and patient-reported outcomes can be readily applied in practice. This convergence of outcome assessment in clinical trials and practice could expedite implementation of "treat-to-target" algorithms, in which therapy is progressively intensified until a specific treatment goal is reached. This approach could improve patient care by reducing rates of disease-related complications, surgery, and hospitalization.
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Affiliation(s)
- Barrett G Levesque
- Division of Gastroenterology, University of California San Diego, La Jolla, California
| | - William J Sandborn
- Division of Gastroenterology, University of California San Diego, La Jolla, California.
| | - Joannie Ruel
- Dr Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Brian G Feagan
- Robarts Clinical Trials, Robarts Research Institute, Department of Medicine, Western University, London, Ontario, Canada
| | - Bruce E Sands
- Dr Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jean-Frederic Colombel
- Dr Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York.
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35
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Al-toma A, Nijeboer P, Bouma G, Visser O, Mulder CJJ. Hematopoietic stem cell transplantation for non-malignant gastrointestinal diseases. World J Gastroenterol 2014; 20:17368-17375. [PMID: 25516648 PMCID: PMC4265595 DOI: 10.3748/wjg.v20.i46.17368] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2014] [Revised: 04/30/2014] [Accepted: 09/30/2014] [Indexed: 02/06/2023] Open
Abstract
Both, autologous and allogeneic hematopoietic stem cell transplantation (HSCT) can be used to cure or ameliorate a variety of malignant and non-malignant diseases. The rationale behind this strategy is based on the concept of immunoablation using high-dose chemotherapy, with subsequent regeneration of naive T-lymphocytes derived from reinfused hematopoietic progenitor cells. In addition, the use of HSCT allows for the administration of high-dose chemotherapy (whether or not combined with immunomodulating agents such as antithymocyte globulin) resulting in a prompt remission in therapy-refractory patients. This review gives an update of the major areas of successful uses of HSCT in non-malignant gastrointestinal disorders. A Medline search has been conducted and all relevant published data were analyzed. HSCT has been proved successful in treating refractory Crohn’s disease (CD). Patients with refractory celiac disease type II and a high risk of developing enteropathy associated T-cell lymphoma have shown promising improvement. Data concerning HSCT and mesenchymal SCT in end-stage chronic liver diseases are encouraging. In refractory autoimmune gastrointestinal diseases high-dose chemotherapy followed by HSCT seems feasible and safe and might result in long-term improvement of disease activity. Mesenchymal SCT for a selected group of CD is promising and may represent a significant therapeutic alternative in treating fistulas in CD.
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Sales-Campos H, Basso PJ, Alves VBF, Fonseca MTC, Bonfá G, Nardini V, Cardoso CRB. Classical and recent advances in the treatment of inflammatory bowel diseases. ACTA ACUST UNITED AC 2014; 48:96-107. [PMID: 25466162 PMCID: PMC4321214 DOI: 10.1590/1414-431x20143774] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2014] [Accepted: 09/25/2014] [Indexed: 02/07/2023]
Abstract
Crohn's disease (CD) and ulcerative colitis (UC) are intestinal disorders that comprise the inflammatory bowel diseases (IBD). These disorders have a significant effect on the quality of life of affected patients and the increasing number of IBD cases worldwide is a growing concern. Because of the overall burden of IBD and its multifactorial etiology, efforts have been made to improve the medical management of these inflammatory conditions. The classical therapeutic strategies aim to control the exacerbated host immune response with aminosalicylates, antibiotics, corticosteroids, thiopurines, methotrexate and anti-tumor necrosis factor (TNF) biological agents. Although successful in the treatment of several CD or UC conditions, these drugs have limited effectiveness, and variable responses may culminate in unpredictable outcomes. The ideal therapy should reduce inflammation without inducing immunosuppression, and remains a challenge to health care personnel. Recently, a number of additional approaches to IBD therapy, such as new target molecules for biological agents and cellular therapy, have shown promising results. A deeper understanding of IBD pathogenesis and the availability of novel therapies are needed to improve therapeutic success. This review describes the overall key features of therapies currently employed in clinical practice as well as novel and future alternative IBD treatment methods.
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Affiliation(s)
- H Sales-Campos
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - P J Basso
- Departamento de Imunologia e Bioquímica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - V B F Alves
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - M T C Fonseca
- Departamento de Imunologia e Bioquímica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - G Bonfá
- Departamento de Imunologia e Bioquímica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - V Nardini
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
| | - C R B Cardoso
- Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil
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37
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Snowden JA, Ansari A, Sachchithanantham S, Jackson G, Thompson N, Lobo A, Sanderson J, Kazmi M. Autologous stem cell transplantation in severe treatment-resistant Crohn's disease: long-term follow-up of UK patients treated on compassionate basis. QJM 2014; 107:871-7. [PMID: 24803477 DOI: 10.1093/qjmed/hcu095] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Although autologous stem cell transplantation (ASCT) may achieve disease control in severe treatment-resistant Crohn's disease (CD), relapse is frequent, and there is little information regarding long-term outcomes in terms of response to subsequent treatments and complications of ASCT. DESIGN Retrospective evaluation of UK patients treated on a compassionate basis from three UK tertiary centres. METHODS We summarize long-term outcomes of six previously unreported patients with severe treatment-resistant CD treated with ASCT according to international guidelines between 2003 and 2009. Median duration of CD before ASCT was 14 (7-22) years. Following stem cell mobilization, patients were treated with high-dose cyclophosphamide (200 mg/kg) and rabbit anti-thymocyte globulin (7.5 mg/kg) followed by ASCT. RESULTS All patients tolerated ASCT with routine toxicities and no treatment-related mortality and are alive at 50-123 months post-ASCT. Clinical and endoscopic remissions of CD were confirmed at 3 months post-ASCT in five patients, although median time to next treatment for inflammatory disease was 10 months (range: 3-16 months). Subsequently, disease control was achieved with previously ineffective and newer treatments, with surgery performed predominantly for pre-existing fibrotic strictures. Two patients became independent of home total parenteral nutrition (TPN). Reported late complications of ASCT included hypothyroidism and ovarian failure. CONCLUSION Long-term follow-up supports the safety and feasibility of ASCT as a means of achieving short-term control of severe CD whilst potentially re-sensitizing the disease to medical therapy and reducing requirements for surgery and TPN. Given the inevitability of relapse, pre-emptive salvage and/or maintenance treatments post-ASCT should be the focus of future trials.
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Affiliation(s)
- J A Snowden
- From the Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Department of Oncology, University of Sheffield, Department of Gastroenterology, East Surrey Hospitals NHS Trust, Redhill, RH1 5RH Department of Haematology, Guy's and St. Thomas' NHS Foundation Trust, London SE1 9RT Department of Haematology, Newcastle University, Newcastle-Upon-Tyne, NE1 7RU Department of Gastroenterology, Freeman Hospital, Newcastle-Upon-Tyne, NE7 7DN Department of Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF and Department of Gastroenterology, Guy's and St. Thomas' NHS Foundation Trust, London, SE1 9RT UK From the Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Department of Oncology, University of Sheffield, Department of Gastroenterology, East Surrey Hospitals NHS Trust, Redhill, RH1 5RH Department of Haematology, Guy's and St. Thomas' NHS Foundation Trust, London SE1 9RT Department of Haematology, Newcastle University, Newcastle-Upon-Tyne, NE1 7RU Department of Gastroenterology, Freeman Hospital, Newcastle-Upon-Tyne, NE7 7DN Department of Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF and Department of Gastroenterology, Guy's and St. Thomas' NHS Foundation Trust, London, SE1 9RT UK
| | - A Ansari
- From the Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Department of Oncology, University of Sheffield, Department of Gastroenterology, East Surrey Hospitals NHS Trust, Redhill, RH1 5RH Department of Haematology, Guy's and St. Thomas' NHS Foundation Trust, London SE1 9RT Department of Haematology, Newcastle University, Newcastle-Upon-Tyne, NE1 7RU Department of Gastroenterology, Freeman Hospital, Newcastle-Upon-Tyne, NE7 7DN Department of Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF and Department of Gastroenterology, Guy's and St. Thomas' NHS Foundation Trust, London, SE1 9RT UK
| | - S Sachchithanantham
- From the Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Department of Oncology, University of Sheffield, Department of Gastroenterology, East Surrey Hospitals NHS Trust, Redhill, RH1 5RH Department of Haematology, Guy's and St. Thomas' NHS Foundation Trust, London SE1 9RT Department of Haematology, Newcastle University, Newcastle-Upon-Tyne, NE1 7RU Department of Gastroenterology, Freeman Hospital, Newcastle-Upon-Tyne, NE7 7DN Department of Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF and Department of Gastroenterology, Guy's and St. Thomas' NHS Foundation Trust, London, SE1 9RT UK
| | - G Jackson
- From the Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Department of Oncology, University of Sheffield, Department of Gastroenterology, East Surrey Hospitals NHS Trust, Redhill, RH1 5RH Department of Haematology, Guy's and St. Thomas' NHS Foundation Trust, London SE1 9RT Department of Haematology, Newcastle University, Newcastle-Upon-Tyne, NE1 7RU Department of Gastroenterology, Freeman Hospital, Newcastle-Upon-Tyne, NE7 7DN Department of Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF and Department of Gastroenterology, Guy's and St. Thomas' NHS Foundation Trust, London, SE1 9RT UK
| | - N Thompson
- From the Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Department of Oncology, University of Sheffield, Department of Gastroenterology, East Surrey Hospitals NHS Trust, Redhill, RH1 5RH Department of Haematology, Guy's and St. Thomas' NHS Foundation Trust, London SE1 9RT Department of Haematology, Newcastle University, Newcastle-Upon-Tyne, NE1 7RU Department of Gastroenterology, Freeman Hospital, Newcastle-Upon-Tyne, NE7 7DN Department of Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF and Department of Gastroenterology, Guy's and St. Thomas' NHS Foundation Trust, London, SE1 9RT UK
| | - A Lobo
- From the Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Department of Oncology, University of Sheffield, Department of Gastroenterology, East Surrey Hospitals NHS Trust, Redhill, RH1 5RH Department of Haematology, Guy's and St. Thomas' NHS Foundation Trust, London SE1 9RT Department of Haematology, Newcastle University, Newcastle-Upon-Tyne, NE1 7RU Department of Gastroenterology, Freeman Hospital, Newcastle-Upon-Tyne, NE7 7DN Department of Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF and Department of Gastroenterology, Guy's and St. Thomas' NHS Foundation Trust, London, SE1 9RT UK
| | - J Sanderson
- From the Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Department of Oncology, University of Sheffield, Department of Gastroenterology, East Surrey Hospitals NHS Trust, Redhill, RH1 5RH Department of Haematology, Guy's and St. Thomas' NHS Foundation Trust, London SE1 9RT Department of Haematology, Newcastle University, Newcastle-Upon-Tyne, NE1 7RU Department of Gastroenterology, Freeman Hospital, Newcastle-Upon-Tyne, NE7 7DN Department of Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF and Department of Gastroenterology, Guy's and St. Thomas' NHS Foundation Trust, London, SE1 9RT UK
| | - M Kazmi
- From the Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Department of Oncology, University of Sheffield, Department of Gastroenterology, East Surrey Hospitals NHS Trust, Redhill, RH1 5RH Department of Haematology, Guy's and St. Thomas' NHS Foundation Trust, London SE1 9RT Department of Haematology, Newcastle University, Newcastle-Upon-Tyne, NE1 7RU Department of Gastroenterology, Freeman Hospital, Newcastle-Upon-Tyne, NE7 7DN Department of Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF and Department of Gastroenterology, Guy's and St. Thomas' NHS Foundation Trust, London, SE1 9RT UK
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A systematic review of measurement of endoscopic disease activity and mucosal healing in Crohn's disease: recommendations for clinical trial design. Inflamm Bowel Dis 2014; 20:1850-61. [PMID: 25029615 DOI: 10.1097/mib.0000000000000131] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Crohn's disease (CD) is a chronic idiopathic inflammatory disorder of the gastrointestinal tract. Recently, mucosal healing has been proposed as a goal of therapy because clinical symptoms are subjective. Evaluative indices that measure endoscopic disease activity are required to define mucosal healing for clinical trials. The primary objective of this systematic review was to assess the existing evaluative indices that measure disease activity in CD and evaluate their role as outcome measures in clinical trials. METHODS A systematic literature review was performed using MEDLINE (Ovid), EMBASE (Ovid), PubMed, the Cochrane Library (CENTRAL), and DDW abstracts to identify randomized controlled trials and controlled clinical trials that used a relevant evaluative index from inception to February 2013. The data obtained from these trials were reviewed and summarized. RESULTS The initial literature searches identified 2300 citations. After duplicates were removed, 1454 studies remained. After application of the apriori inclusion and exclusion criteria, 109 articles were included and 3 were identified with handsearches. In total, 9 evaluative indices for CD were identified and reviewed. The Crohn's Disease Endoscopic Index of Severity (CDEIS) and the Simple Endoscopic Score in Crohn's Disease (SES-CD) are indices with the most extensively described operating properties. CONCLUSIONS Both the endoscopic evaluative instrument selected and the definition chosen for mucosal healing affect the validity of assessing endoscopic disease activity during a clinical trial for CD. Currently, the CDEIS and SES-CD have the most data regarding operating properties; however, further validation is required.
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Martínez-Montiel MDP, Gómez-Gómez GJ, Flores AI. Therapy with stem cells in inflammatory bowel disease. World J Gastroenterol 2014; 20:1211-1227. [PMID: 24574796 PMCID: PMC3921504 DOI: 10.3748/wjg.v20.i5.1211] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 11/23/2013] [Accepted: 01/06/2014] [Indexed: 02/07/2023] Open
Abstract
Inflammatory bowel disease (IBD) affects a part of the young population and has a strong impact upon quality of life. The underlying etiology is not known, and the existing treatments are not curative. Furthermore, a significant percentage of patients are refractory to therapy. In recent years there have been great advances in our knowledge of stem cells and their therapeutic applications. In this context, autologous hematopoietic stem cell transplantation (HSCT) has been used in application to severe refractory Crohn's disease (CD), with encouraging results. Allogenic HSCT would correct the genetic defects of the immune system, but is currently not accepted for the treatment of IBD because of its considerable risks. Mesenchymal stem cells (MSCs) have immune regulatory and regenerative properties, and low immunogenicity (both autologous and allogenic MSCs). Based on these properties, MSCs have been used via the systemic route in IBD with promising results, though it is still too soon to draw firm conclusions. Their local administration in perianal CD is the field where most progress has been made in recent years, with encouraging results. The next few years will be decisive for defining the role of such therapy in the management of IBD.
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Jain S, Gozdziak P, Morgan A, Burt RK. Remission of Crohn’s disease after cord blood transplantation for leukocyte adhesion deficiency type 1. Bone Marrow Transplant 2013; 48:1006-7. [DOI: 10.1038/bmt.2012.274] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
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Crohn's disease: Cell transplant stems IBD. Nat Rev Gastroenterol Hepatol 2012; 9:618. [PMID: 22986310 DOI: 10.1038/nrgastro.2012.184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
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