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      Safety, tolerability and potential efficacy of injection of autologous adipose-derived stromal vascular fraction in the fingers of patients with systemic sclerosis: an open-label phase I trial

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          Abstract

          Background

          In patients with systemic sclerosis (scleroderma, SSc), impaired hand function greatly contributes to disability and reduced quality of life, and is insufficiently relieved by currently available therapies. Adipose tissue-derived stromal vascular fraction (SVF) is increasingly recognised as an easily accessible source of regenerative cells with therapeutic potential in ischaemic or autoimmune diseases. We aimed to measure for the first time the safety, tolerability and potential efficacy of autologous SVF cells local injections in patients with SSc with hand disability.

          Methods

          We did an open-label, single arm, at one study site with 6-month follow-up among 12 female SSc patients with Cochin Hand Function Scale score >20/90. Autologous SVF was obtained from lipoaspirates, using an automated processing system, and subsequently injected into the subcutaneous tissue of each finger in contact with neurovascular pedicles. Primary outcome was the number and the severity of adverse events related to SVF-based therapy. Secondary endpoints were changes in hand disability and fibrosis, vascular manifestations, pain and quality of life from baseline to 2 and 6 months after cell therapy.

          Findings

          All enrolled patients had surgery, and there were no dropouts or patients lost to follow-up. No severe adverse events occurred during the procedure and follow-up. Four minor adverse events were reported and resolved spontaneously. A significant improvement in hand disability and pain, Raynaud's phenomenon, finger oedema and quality of life was observed.

          Interpretation

          This study outlines the safety of the autologous SVF cells injection in the hands of patients with SSc. Preliminary assessments at 6 months suggest potential efficacy needing confirmation in a randomised placebo-controlled trial on a larger population.

          Funding

          GFRS (Groupe Francophone de Recherche sur la Sclérodermie).

          Clinical Trials number

          NCT01813279.

          Related collections

          Most cited references18

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          Comparison of allogeneic vs autologous bone marrow–derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial.

          Mesenchymal stem cells (MSCs) are under evaluation as a therapy for ischemic cardiomyopathy (ICM). Both autologous and allogeneic MSC therapies are possible; however, their safety and efficacy have not been compared. To test whether allogeneic MSCs are as safe and effective as autologous MSCs in patients with left ventricular (LV) dysfunction due to ICM. A phase 1/2 randomized comparison (POSEIDON study) in a US tertiary-care referral hospital of allogeneic and autologous MSCs in 30 patients with LV dysfunction due to ICM between April 2, 2010, and September 14, 2011, with 13-month follow-up. Twenty million, 100 million, or 200 million cells (5 patients in each cell type per dose level) were delivered by transendocardial stem cell injection into 10 LV sites. Thirty-day postcatheterization incidence of predefined treatment-emergent serious adverse events (SAEs). Efficacy assessments included 6-minute walk test, exercise peak VO2, Minnesota Living with Heart Failure Questionnaire (MLHFQ), New York Heart Association class, LV volumes, ejection fraction (EF), early enhancement defect (EED; infarct size), and sphericity index. Within 30 days, 1 patient in each group (treatment-emergent SAE rate, 6.7%) was hospitalized for heart failure, less than the prespecified stopping event rate of 25%. The 1-year incidence of SAEs was 33.3% (n = 5) in the allogeneic group and 53.3% (n = 8) in the autologous group (P = .46). At 1 year, there were no ventricular arrhythmia SAEs observed among allogeneic recipients compared with 4 patients (26.7%) in the autologous group (P = .10). Relative to baseline, autologous but not allogeneic MSC therapy was associated with an improvement in the 6-minute walk test and the MLHFQ score, but neither improved exercise VO2 max. Allogeneic and autologous MSCs reduced mean EED by −33.21% (95% CI, −43.61% to −22.81%; P < .001) and sphericity index but did not increase EF. Allogeneic MSCs reduced LV end-diastolic volumes. Low-dose concentration MSCs (20 million cells) produced greatest reductions in LV volumes and increased EF. Allogeneic MSCs did not stimulate significant donor-specific alloimmune reactions. In this early-stage study of patients with ICM, transendocardial injection of allogeneic and autologous MSCs without a placebo control were both associated with low rates of treatment-emergent SAEs, including immunologic reactions. In aggregate, MSC injection favorably affected patient functional capacity, quality of life, and ventricular remodeling. clinicaltrials.gov Identifier: NCT01087996.
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            Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee.

            (1980)
            A multicenter, ongoing study of early-diagnosed cases of systemic sclerosis and comparison patients with systemic lupus erythematosus, polymyositis/dermatomyositis, and Raynaud's phenomenon was conducted in order to develop classification criteria for systemic sclerosis. Preliminary criteria are proposed namely, the finding of either the sole major criterion, i.e., proximal scleroderma, or two or more of the minor criteria, i.e., 1) sclerodactyly, 2) digital pitting scars of fingertips or loss of substance of the distal finger pad, and 3) bilateral basilar pulmonary fibrosis. When applied to the case and comparison patients included in this study, these proposed criteria had a 97% sensitivity for definite systemic sclerosis and 98% specificity.
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              Novel autologous cell therapy in ischemic limb disease through growth factor secretion by cultured adipose tissue-derived stromal cells.

              The delivery of autologous progenitor cells into ischemic tissue of patients is emerging as a novel therapeutic option. Here, we report the potential impact of cultured adipose tissue-derived cells (ADSC) on angiogenic cell therapy. ADSC were isolated from C57Bl/6 mouse inguinal adipose tissue and showed high expression of ScaI and CD44, but not c-kit, Lin, CD34, CD45, CD11b, and CD31, compatible with that of mesenchymal stem cells from bone marrow. In coculture conditions with ADSC and human aortic endothelial cells (ECs) under treatment with growth factors, ADSC significantly increased EC viability, migration and tube formation mainly through secretion of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF). At 4 weeks after transplantation of ADSC into the ischemic mouse hindlimb, the angiogenic scores were improved in the ADSC-treated group, which were evaluated with blood flow by laser Doppler imaging (LDI) and capillary density by immunostaining with anti-CD31 antibody. However, injected ADSC did not correspond to CD31, von Willebrand factor, and alpha-smooth muscle actin-positive cells in ischemic tissue. These adipose tissue-derived cells demonstrated potential as angiogenic cell therapy for ischemic disease, which appears to be mainly achieved by their ability to secrete angiogenic growth factors.
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                Author and article information

                Journal
                Ann Rheum Dis
                Ann. Rheum. Dis
                annrheumdis
                ard
                Annals of the Rheumatic Diseases
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                0003-4967
                1468-2060
                December 2015
                11 August 2014
                : 74
                : 12
                : 2175-2182
                Affiliations
                [1 ]Internal Medicine Department, Assistance Publique Hôpitaux de Marseilles (AP-HM), Aix-Marseilles University , Marseilles, France
                [2 ]Vascular Research Center Marseille, INSERM UMRS-1076, Aix-Marseilles University , Marseilles, France
                [3 ]CIC- CPCET, Assistance Publique Hôpitaux de Marseilles (AP-HM), Aix-Marseilles University , Marseilles, France
                [4 ]Plastic Surgery Department, Assistance Publique Hôpitaux de Marseilles (AP-HM), Aix-Marseilles University , Marseilles, France
                [5 ]Cell Therapy Facility & Inserm CBT 510, Institut Paoli Calmettes , Marseilles, France
                [6 ]Department of Radiology, Assistance Publique Hôpitaux de Marseille (AP-HM), Aix-Marseilles University , Marseilles, France
                [7 ]Délégation de la Recherche et de l'Innovation, Assistance Publique Hôpitaux de Marseilles (AP-HM) , Marseilles, France
                [8 ]Department of Dermatology, Assistance Publique Hôpitaux de Marseilles (AP-HM), Aix-Marseilles University , Marseilles, France
                [9 ]Culture and Cell Therapy Laboratory, INSERM CBT 510, Assistance Publique Hôpitaux de Marseilles (AP-HM), Aix-Marseilles University , Marseilles, France
                [10 ]Hematology and Vascular Biology Laboratory, Assistance Publique Hôpitaux de Marseilles (AP-HM), Aix-Marseilles University , Marseilles, France
                Author notes

                Handling editor Tore K Kvien

                [Correspondence to ] Professor Brigitte Granel, North Hospital, Assistance Publique Hôpitaux de Marseilles (AP-HM), Marseilles 139015, France; bgranel@ 123456ap-hm.fr
                Article
                annrheumdis-2014-205681
                10.1136/annrheumdis-2014-205681
                4680117
                25114060
                d040359d-1872-4ada-9de8-f3819ee3ee27
                Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

                History
                : 4 April 2014
                : 15 July 2014
                : 20 July 2014
                Categories
                1506
                Clinical and Epidemiological Research
                Extended report
                Custom metadata
                unlocked

                Immunology
                autoimmune diseases,systemic sclerosis,treatment
                Immunology
                autoimmune diseases, systemic sclerosis, treatment

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