Expanded allogeneic adipose-derived stem cells (eASCs) for the treatment of complex perianal fistula in Crohn’s disease: results from a multicenter phase I/IIa clinical trial
01 Mar 2013-International Journal of Colorectal Disease (Springer-Verlag)-Vol. 28, Iss: 3, pp 313-323
TL;DR: Locally injected eASCs appear to be a simple, safe, and beneficial therapy for perianal fistula in Crohn’s disease patients, and additional studies are needed to further confirm the efficacy of the eASC.
Abstract: Purpose
The management of perianal fistula in patients with Crohn’s disease is an extremely challenging medical problem as many fistulas do not respond to available treatments The objectives were to assess the safety and efficacy of a suspension of expanded adipose-derived allogeneic mesenchymal stem cells (eASCs) for the treatment of complex perianal fistula in Crohn’s disease
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Newcastle University1, Newcastle upon Tyne Hospitals NHS Foundation Trust2, University of Exeter3, University of Cambridge4, Chelsea and Westminster Hospital NHS Foundation Trust5, Imperial College London6, Royal Liverpool and Broadgreen University Hospital NHS Trust7, University of Manchester8, Pennine Acute Hospitals NHS Trust9, King's College London10, Guy's and St Thomas' NHS Foundation Trust11, Queen Mary University of London12, Barts Health NHS Trust13, University of Leeds14, Leeds Teaching Hospitals NHS Trust15, Royal College of Surgeons in Ireland16, University of Edinburgh17, Western General Hospital18, University Hospitals Bristol NHS Foundation Trust19, University of Glasgow20, Glasgow Royal Infirmary21, Queen Elizabeth Hospital Birmingham22, University of Birmingham23, University College London24, University College London Hospitals NHS Foundation Trust25, Brighton and Sussex University Hospitals NHS Trust26, Brighton and Sussex Medical School27, University of Wolverhampton28, University Hospital of Wales29
TL;DR: Comprehensive up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and postoperative management, as well as structure and function of the multidisciplinary team and integration between primary and secondary care.
Abstract: Ulcerative colitis and Crohn’s disease are the principal forms of inflammatory bowel disease. Both represent chronic inflammation of the gastrointestinal tract, which displays heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management relies on understanding and tailoring evidence-based interventions by clinicians in partnership with patients. This guideline for management of inflammatory bowel disease in adults over 16 years of age was developed by Stakeholders representing UK physicians (British Society of Gastroenterology), surgeons (Association of Coloproctology of Great Britain and Ireland), specialist nurses (Royal College of Nursing), paediatricians (British Society of Paediatric Gastroenterology, Hepatology and Nutrition), dietitians (British Dietetic Association), radiologists (British Society of Gastrointestinal and Abdominal Radiology), general practitioners (Primary Care Society for Gastroenterology) and patients (Crohn’s and Colitis UK). A systematic review of 88 247 publications and a Delphi consensus process involving 81 multidisciplinary clinicians and patients was undertaken to develop 168 evidence- and expert opinion-based recommendations for pharmacological, non-pharmacological and surgical interventions, as well as optimal service delivery in the management of both ulcerative colitis and Crohn’s disease. Comprehensive up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and postoperative management, as well as structure and function of the multidisciplinary team and integration between primary and secondary care. Twenty research priorities to inform future clinical management are presented, alongside objective measurement of priority importance, determined by 2379 electronic survey responses from individuals living with ulcerative colitis and Crohn’s disease, including patients, their families and friends.
1,140 citations
TL;DR: Cx601 is an effective and safe treatment for complex perianal fistulas in patients with Crohn's disease who did not respond to conventional or biological treatments, or both.
725 citations
Humanitas University1, University College Dublin2, Autonomous University of Madrid3, Cambridge University Hospitals NHS Foundation Trust4, Winterthur Museum, Garden and Library5, University of Basel6, Catholic University of the Sacred Heart7, Aarhus University Hospital8, University of Copenhagen9, Royal Liverpool University Hospital10, Aalborg University11, Mater Dei Hospital12, University of Bologna13, Barts Health NHS Trust14, Comenius University in Bratislava15, Sheba Medical Center16, University of Porto17, McMaster University18, Linköping University19, Seconda Università degli Studi di Napoli20, Katholieke Universiteit Leuven21, University of Padua22, Maastricht University Medical Centre23, Beaujon Hospital24, University of Zurich25, Imperial College London26
TL;DR: The present article addresses surgical management, including preoperative aspects and drug management before surgery, and provides technical advice for a variety of common clinical situations.
Abstract: This article is the second in a series of two publications relating to the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the management of Crohn's disease. The first article covers medical management; the present article addresses surgical management, including preoperative aspects and drug management before surgery. It also provides technical advice for a variety of common clinical situations. Both articles together represent the evidence-based recommendations of the ECCO for Crohn's disease and an update of previous guidelines.
563 citations
TL;DR: Administration of allogeneic adipose-derived MSCs appears to be safe and feasible in the treatment of ARDS, and further optimization of this strategy will probably be required to reach the goal of reduced alveolar epithelial injury in ARDS.
Abstract: Recent studies have demonstrated that mesenchymal stem cells (MSCs) modulate the immune response and reduce lung injury in animal models. Currently, no clinical studies of the effects of MSCs in acute respiratory distress syndrome (ARDS) exist. The objectives of this study were first to examine the possible adverse events after systemic administration of allogeneic adipose-derived MSCs in ARDS patients and second to determine potential efficacy of MSCs on ARDS. Twelve adult patients meeting the Berlin definition of acute respiratory distress syndrome with a PaO2/FiO2 ratio of < 200 were randomized to receive allogeneic adipose-derived MSCs or placebo in a 1:1 fashion. Patients received one intravenous dose of 1 × 106 cells/kg of body weight or saline. Possible side effects were monitored after treatment. Acute lung injury biomarkers, including IL-6, IL-8 and surfactant protein D (SP-D), were examined to determine the effects of MSCs on lung injury and inflammation. There were no infusion toxicities or serious adverse events related to MSCs administration and there were no significant differences in the overall number of adverse events between the two groups. Length of hospital stay, ventilator-free days and ICU-free days at day 28 after treatment were similar. There were no changes in biomarkers examined in the placebo group. In the MSCs group, serum SP-D levels at day 5 were significantly lower than those at day 0 (p = 0.027) while the changes in IL-8 levels were not significant. The IL-6 levels at day 5 showed a trend towards lower levels as compared with day 0, but this trend was not statistically significant (p = 0.06). Administration of allogeneic adipose-derived MSCs appears to be safe and feasible in the treatment of ARDS. However, the clinical effect with the doses of MSCs used is weak, and further optimization of this strategy will probably be required to reach the goal of reduced alveolar epithelial injury in ARDS. Clinical trials.gov, NCT01902082
335 citations
Cites background from "Expanded allogeneic adipose-derived..."
...3% of the patients achieving complete closure of the treated fistula [7]....
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...Allogeneic MSCs have been applied to treat graft-versus-host diseases [4], myocardial infarction [5], autoimmune diseases [6], and inflammatory bowel diseases [7]....
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TL;DR: A consensus on the classification, diagnosis and multidisciplinary treatment of perianal fistulising Crohn's disease (pCD), based on best available evidence is developed.
Abstract: Objective To develop a consensus on the classification, diagnosis and multidisciplinary treatment of perianal fistulising Crohn’s disease (pCD), based on best available evidence. Methods Based on a systematic literature review, statements were formed, discussed and approved in multiple rounds by the 20 working group participants. Consensus was defined as at least 80% agreement among voters. Evidence was assessed using the modified GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria. Results Highest diagnostic accuracy can only be established if a combination of modalities is used. Drainage of sepsis is always first line therapy before initiating immunosuppressive treatment. Mucosal healing is the goal in the presence of proctitis. Whereas antibiotics and thiopurines have a role as adjunctive treatments in pCD, anti-tumour necrosis factor (anti-TNF) is the current gold standard. The efficacy of infliximab is best documented although adalimumab and certolizumab pegol are moderately effective. Oral tacrolimus could be used in patients failing anti-TNF therapy. Definite surgical repair is only of consideration in the absence of luminal inflammation. Conclusions Based on a multidisciplinary approach, items relevant for fistula management were identified and algorithms on diagnosis and treatment of pCD were developed.
302 citations
References
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TL;DR: The data demonstrate that autologous or allogeneic BMSCs strongly suppress T-lymphocyte proliferation, this phenomenon that is triggered by both cellular as well as nonspecific mitogenic stimuli has no immunologic restriction, and T-cell inhibition is not due to induction of apoptosis and is likely due to the production of soluble factors.
3,127 citations
Harvard University1, University of British Columbia2, University of Manitoba3, University of Rochester4, University of Western Ontario5, University of Alberta6, Imperial College London7, Washington University in St. Louis8, Duke University9, Tel Aviv Sourasky Medical Center10, Katholieke Universiteit Leuven11, McGill University12, University of Amsterdam13
TL;DR: Patients with fistulizing Crohn's disease who have a response to induction therapy with inflIXimab have an increased likelihood of a sustained response over a 54-week period if infliximab treatment is continued every 8 weeks.
Abstract: BACKGROUND: Infliximab, a monoclonal antibody against tumor necrosis factor, is an effective maintenance therapy for patients with Crohn's disease without fistulas. It is not known whether infliximab is an effective maintenance therapy for patients with fistulas. METHODS: We performed a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the efficacy of infliximab maintenance therapy in 306 adult patients with Crohn's disease and one or more draining abdominal or perianal fistulas of at least three months' duration. Patients received 5 mg of infliximab per kilogram of body weight intravenously on weeks 0, 2, and 6. A total of 195 patients who had a response at weeks 10 and 14 and 87 patients who had no response were then randomly assigned to receive placebo or 5 mg of infliximab per kilogram every eight weeks and to be followed to week 54. The primary analysis was the time to the loss of response among patients who had a response at week 14 and underwent randomization. RESULTS: The time to loss of response was significantly longer for patients who received infliximab maintenance therapy than for those who received placebo maintenance (more than 40 weeks vs. 14 weeks, P<0.001). At week 54, 19 percent of patients in the placebo maintenance group had a complete absence of draining fistulas, as compared with 36 percent of patients in the infliximab maintenance group (P=0.009). CONCLUSIONS: Patients with fistulizing Crohn's disease who have a response to induction therapy with infliximab have an increased likelihood of a sustained response over a 54-week period if infliximab treatment is continued every 8 weeks.
2,006 citations
"Expanded allogeneic adipose-derived..." refers background in this paper
...To date, only the monoclonal antibody infliximab has demonstrated efficacy for the treatment of anal fistula in Crohn’s disease patients in a RCT [28]....
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...Data has been derived from post hoc analyses of RCT in which IMMs were used for treatment of active luminal disease....
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...Although antibiotics are commonly used as firstline therapy [25], their efficacy has never been adequately demonstrated in randomized clinical trials (RCT) [26]....
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...Immunosuppressants (IMMs) are commonly used as second-line therapy, but again no RCT assessing the efficacy of this treatment exists....
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TL;DR: The results further support the potential therapeutic use of hMSCs in immune-mediated disorders, including those in which B cells play a major role.
1,652 citations
TL;DR: Undifferentiated and differentiated MSC do not elicit alloreactive lymphocyte proliferative responses and modulate immune responses, and the findings support that MSC can be transplantable between HLA-incompatible individuals.
1,650 citations
"Expanded allogeneic adipose-derived..." refers background in this paper
...This immune privilege of ASCs therefore supports the feasibility of allogeneic treatments without the requirement of suppression of host immunity [17, 18]....
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TL;DR: It is suggested that MSCs physically hinder T cells from the contact with APCs in a noncognate fashion and inhibit naive and memory T-cell responses to their cognate antigens.
1,575 citations