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Farge D, Pugnet G, Allez M, Castilla-Llorente C, Chatelus E, Cintas P, Faucher-Barbey C, Labauge P, Labeyrie C, Lioure B, Maria A, Michonneau D, Puyade M, Talouarn M, Terriou L, Treton X, Wojtasik G, Zephir H, Marjanovic Z. French protocol for the diagnosis and management of hematopoietic stem cell transplantation in autoimmune diseases. Rev Med Interne 2024; 45:79-99. [PMID: 38220493 DOI: 10.1016/j.revmed.2023.12.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 12/29/2023] [Indexed: 01/16/2024]
Abstract
Hematopoietic stem cell transplantation (HSCT) for severe ADs was developed over the past 25years and is now validated by national and international medical societies for severe early systemic sclerosis (SSc) and relapsing-remitting multiple sclerosis (MS) and available as part of routine care in accredited center. HSCT is also recommended, with varying levels of evidence, as an alternative treatment for several ADs, when refractory to conventional therapy, including specific cases of connective tissue diseases or vasculitis, inflammatory neurological diseases, and more rarely severe refractory Crohn's disease. The aim of this document was to provide guidelines for the current indications, procedures and follow-up of HSCT in ADs. Patient safety considerations are central to guidance on patient selection and conditioning, always validated at the national MATHEC multidisciplinary team meeting (MDTM) based on recent (less than 3months) thorough patient evaluation. HSCT procedural aspects and follow-up are then carried out within appropriately experienced and Joint Accreditation Committee of International Society for Cellular Therapy and SFGM-TC accredited centres in close collaboration with the ADs specialist. These French recommendations were performed according to HAS/FAI2R standard operating procedures and coordinated by the Île-de-France MATHEC Reference Centre for Rare Systemic Autoimmune Diseases (CRMR MATHEC) within the Filière FAI2R and in association with the Filière MaRIH. The task force consisted of 3 patients and 64 clinical experts from various specialties and French centres. These data-derived and consensus-derived recommendations will help clinicians to propose HSCT for their severe ADs patients in an evidence-based way. These recommendations also give directions for future clinical research in this area. These recommendations will be updated according to newly emerging data. Of note, other cell therapies that have not yet been approved for clinical practice or are the subject of ongoing clinical research will not be addressed in this document.
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Affiliation(s)
- D Farge
- AP-HP, hôpital St-Louis, centre de référence des maladies auto-immunes systémiques rares d'Île-de-France MATHEC (FAI2R), unité de Médecine Interne (UF 04) : CRMR MATHEC, maladies auto-immunes et thérapie cellulaire (UF 04), 1, avenue Claude-Vellefaux, 75010 Paris, France; Université de Paris, IRSL, Recherche clinique appliquée à l'hématologie, URP-3518, 75010 Paris, France; Department of Medicine, McGill University, H3A 1A1, Montreal, Canada.
| | - G Pugnet
- Service de médecine interne et immunologie clinique, pôle hospitalo-universitaire des maladies digestives, CHU Rangueil, 1, avenue du Pr-Jean-Poulhès, 31059 Toulouse cedex 9, France
| | - M Allez
- AP-HP, hôpital Saint-Louis, service d'hépato-gastro-entérologie, 1, avenue Claude-Vellefaux, 75010 Paris, France
| | - C Castilla-Llorente
- Gustave-Roussy cancer center, département d'hématologie, 114, rue Édouard-Vaillant, 94800 Villejuif, France
| | - E Chatelus
- Département de rhumatologie, hôpitaux universitaires de Strasbourg, Strasbourg, France; Centre de référence des maladies auto-immunes systémiques rares de l'Est et du Sud-Ouest, Strasbourg, France
| | - P Cintas
- CHU Toulouse Purpan, service de neurologie, place du Dr-Baylac, 31059 Toulouse cedex 9, France
| | - C Faucher-Barbey
- Direction prélèvements et greffes de CSH, Direction médicale et scientifique, Agence de la biomédecine, 93212 St-Denis/La Plaine, France
| | - P Labauge
- CRC SEP, service de neurologie, CHU de Montpellier, 34295 Montpellier cedex 5, France
| | - C Labeyrie
- AP-HP, CHU de Bicêtre, service de neurologie, 78, rue du Général-Leclerc, 94270 Le Kremlin-Bicêtre, France
| | - B Lioure
- Département d'onco-hématologie, université de Strasbourg, ICANS, Strasbourg, France
| | - A Maria
- Médecine interne & immuno-oncologie (MedI2O), Institute for Regenerative Medicine & Biotherapy (IRMB), hôpital Saint-Éloi, CHU de Montpellier, 80, avenue Augustin-Fliche, Montpellier, France; IRMB, Inserm U1183, hôpital Saint-Éloi, CHU de Montpellier, 34295 Montpellier, France
| | - D Michonneau
- Université de Paris, IRSL, Recherche clinique appliquée à l'hématologie, URP-3518, 75010 Paris, France; Service d'hématologie-greffe, AP-HP, hôpital Saint-Louis, institut de recherche Saint-Louis, Paris, France
| | - M Puyade
- CHU de Poitiers, service de médecine interne, 2, rue de La-Miletrie, 86021 Poitiers, France
| | - M Talouarn
- AP-HP, hôpital Saint-Antoine, service d'hématologie clinique et thérapie cellulaire, 184, rue du Faubourg-Saint-Antoine, 75012 Paris, France
| | - L Terriou
- CHU de Lille, département de médecine interne et immunologie clinique, 59000 Lille, France; Centre de référence des maladies auto-immunes et auto-inflammatoires rares (CERAINO), 59000 Lille, France
| | - X Treton
- Université de Paris, hôpital Beaujon, service de gastro-entérologie, MICI et assistance nutritive, DMU DIGEST, 100, boulevard Leclerc, 92110 Clichy, France
| | - G Wojtasik
- Université de Lille, Inserm, CHU de Lille, service de médecine interne et immunologie clinique, Centre de référence des maladies auto-immunes systémiques rares du Nord et Nord-Ouest de France (CeRAINO), U1286 - INFINITE - Institut de recherche translationnelle sur l'inflammation, Lille, France
| | - H Zephir
- CHU de Lille, université de Lille, pôle des neurosciences et de l'appareil locomoteur, Lille Inflammation Research International Center (LIRIC), UMR 995, rue Émile-Laine, 59000 Lille, France
| | - Z Marjanovic
- AP-HP, hôpital Saint-Antoine, service d'hématologie clinique et thérapie cellulaire, 184, rue du Faubourg-Saint-Antoine, 75012 Paris, France
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Penglase R, Girgis L, Englert H, Brennan X, Jabbour A, Kotlyar E, Ma D, Moore J. Cardiotoxicity in autologous haematopoietic stem cell transplantation for systemic sclerosis. JOURNAL OF SCLERODERMA AND RELATED DISORDERS 2023; 8:87-100. [PMID: 37287946 PMCID: PMC10242691 DOI: 10.1177/23971983221145639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 11/15/2022] [Indexed: 09/20/2023]
Abstract
Autologous haematopoietic stem cell transplantation is now well-established as an effective treatment for severe systemic sclerosis with clear demonstration of favourable end-organ and survival outcomes. Treatment-related cardiotoxicity remains the predominant safety concern and contraindicates autologous haematopoietic stem cell transplantation in patients with severe cardiopulmonary disease. In this review, we describe the cardiovascular outcomes of autologous haematopoietic stem cell transplantation recipients, discuss the potential mechanisms of cardiotoxicity and propose future mitigating strategies.
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Affiliation(s)
- Ross Penglase
- Department of Rheumatology, St. Vincent’s Hospital Sydney, Darlinghurst, NSW, Australia
- University of New South Wales, Sydney, NSW, Australia
- St. Vincent’s Centre for Applied Medical Research, Darlinghurst, NSW, Australia
| | - Laila Girgis
- Department of Rheumatology, St. Vincent’s Hospital Sydney, Darlinghurst, NSW, Australia
- University of New South Wales, Sydney, NSW, Australia
- St. Vincent’s Centre for Applied Medical Research, Darlinghurst, NSW, Australia
| | - Helen Englert
- Department of Haematology and BM Transplantation, St. Vincent’s Hospital Sydney, Darlinghurst, NSW, Australia
| | - Xavier Brennan
- Department of Cardiology and Heart and Lung Transplantation, St. Vincent’s Hospital Sydney, Darlinghurst, NSW, Australia
| | - Andrew Jabbour
- University of New South Wales, Sydney, NSW, Australia
- Department of Cardiology and Heart and Lung Transplantation, St. Vincent’s Hospital Sydney, Darlinghurst, NSW, Australia
| | - Eugene Kotlyar
- University of New South Wales, Sydney, NSW, Australia
- Department of Cardiology and Heart and Lung Transplantation, St. Vincent’s Hospital Sydney, Darlinghurst, NSW, Australia
| | - David Ma
- University of New South Wales, Sydney, NSW, Australia
- St. Vincent’s Centre for Applied Medical Research, Darlinghurst, NSW, Australia
- Department of Haematology and BM Transplantation, St. Vincent’s Hospital Sydney, Darlinghurst, NSW, Australia
| | - John Moore
- University of New South Wales, Sydney, NSW, Australia
- St. Vincent’s Centre for Applied Medical Research, Darlinghurst, NSW, Australia
- Department of Haematology and BM Transplantation, St. Vincent’s Hospital Sydney, Darlinghurst, NSW, Australia
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Higashitani K, Takase-Minegishi K, Yoshimi R, Kirino Y, Hamada N, Nagai H, Hagihara M, Matsumoto K, Namkoong H, Horita N, Nakajima H. Benefits and risks of haematopoietic stem cell transplantation for systemic sclerosis: A systematic review and meta-analysis. Mod Rheumatol 2023; 33:330-337. [PMID: 35285885 DOI: 10.1093/mr/roac026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/07/2022] [Accepted: 03/09/2022] [Indexed: 11/12/2022]
Abstract
OBJECTIVES We aimed to evaluate the efficacy and safety of haematopoietic stem cell transplantation (HSCT) in patients with systemic sclerosis. METHODS A systematic literature review and meta-analysis were carried out. We compared survival outcomes using the Kaplan-Meier method with patient-level data between HSCT and intravenous pulse cyclophosphamide. Additionally, the incidence rate of treatment-related deaths with HSCT was pooled using a random-effect model. RESULTS Of the 2091 articles screened, 22 were included: 3 randomized controlled trials and 19 observational studies. HSCT studies showed significant improvement in the skin thickness score and lung function. Despite treatment-related deaths being higher in HSCT than in intravenous pulse cyclophosphamide, the Kaplan-Meier analysis showed a high survival rate of 2 years post-transplant (log-rank, P = 0.004). The pooled frequency of transplant-related death from 700 systemic sclerosis patients was 6.30% (95% confidence interval 4.21-8.38). However, the estimated frequency of treatment-related deaths has been reducing over the last decade. CONCLUSIONS HSCT is an effective treatment for systemic sclerosis, but the optimal indications must be carefully determined by balancing the risks.
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Affiliation(s)
- Kana Higashitani
- Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Kaoru Takase-Minegishi
- Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Ryusuke Yoshimi
- Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yohei Kirino
- Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Naoki Hamada
- Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Hideto Nagai
- Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Maki Hagihara
- Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Kenji Matsumoto
- Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Ho Namkoong
- Department of Infectious Diseases, Keio University School of Medicine, Tokyo, Japan
| | - Nobuyuki Horita
- Chemotherapy Center, Yokohama City University Hospital, Yokohama, Japan
| | - Hideaki Nakajima
- Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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Xue E, Minniti A, Alexander T, Del Papa N, Greco R, on behalf of The Autoimmune Diseases Working Party (ADWP) of the European Society for Blood and Marrow Transplantation (EBMT). Cellular-Based Therapies in Systemic Sclerosis: From Hematopoietic Stem Cell Transplant to Innovative Approaches. Cells 2022; 11:3346. [PMID: 36359742 PMCID: PMC9658618 DOI: 10.3390/cells11213346] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 10/19/2022] [Accepted: 10/19/2022] [Indexed: 08/28/2023] Open
Abstract
Systemic sclerosis (SSc) is a systemic disease characterized by autoimmune responses, vasculopathy and tissue fibrosis. The pathogenic mechanisms involve a wide range of cells and soluble factors. The complexity of interactions leads to heterogeneous clinical features in terms of the extent, severity, and rate of progression of skin fibrosis and internal organ involvement. Available disease-modifying drugs have only modest effects on halting disease progression and may be associated with significant side effects. Therefore, cellular therapies have been developed aiming at the restoration of immunologic self-tolerance in order to provide durable remissions or to foster tissue regeneration. Currently, SSc is recommended as the 'standard indication' for autologous hematopoietic stem cell transplantation by the European Society for Blood and Marrow Transplantation. This review provides an overview on cellular therapies in SSc, from pre-clinical models to clinical applications, opening towards more advanced cellular therapies, such as mesenchymal stem cells, regulatory T cells and potentially CAR-T-cell therapies.
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Affiliation(s)
- Elisabetta Xue
- Hematopoietic and Bone Marrow Transplant Unit, San Raffaele Hospital, 20132 Milan, Italy
| | - Antonina Minniti
- Department of Rheumatology, ASST G. Pini-CTO, 20122 Milan, Italy
| | - Tobias Alexander
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Rheumatology and Clinical Immunology, 10117 Berlin, Germany
- Deutsches Rheuma-Forschungszentrum (DRFZ), an Institute of the Leibniz Association, 10117 Berlin, Germany
| | | | - Raffaella Greco
- Hematopoietic and Bone Marrow Transplant Unit, San Raffaele Hospital, 20132 Milan, Italy
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Kawashima-Vasconcelos MY, Santana-Gonçalves M, Zanin-Silva DC, Malmegrim KCR, Oliveira MC. Reconstitution of the immune system and clinical correlates after stem cell transplantation for systemic sclerosis. Front Immunol 2022; 13:941011. [PMID: 36032076 PMCID: PMC9403547 DOI: 10.3389/fimmu.2022.941011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 07/25/2022] [Indexed: 11/13/2022] Open
Abstract
Systemic sclerosis (SSc) is a chronic autoimmune disease that includes fibrosis, diffuse vasculopathy, inflammation, and autoimmunity. Autologous hematopoietic stem cell transplantation (auto-HSCT) is considered for patients with severe and progressive SSc. In recent decades, knowledge about patient management and clinical outcomes after auto-HSCT has significantly improved. Mechanistic studies have contributed to increasing the comprehension of how profound and long-lasting are the modifications to the immune system induced by transplantation. This review revisits the immune monitoring studies after auto-HSCT for SSc patients and how they relate to clinical outcomes. This understanding is essential to further improve clinical applications of auto-HSCT and enhance patient outcomes.
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Affiliation(s)
- Marianna Y. Kawashima-Vasconcelos
- Center for Cell-Based Therapy, Regional Hemotherapy Center of the Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
- Internal Medicine Graduate Program, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Maynara Santana-Gonçalves
- Center for Cell-Based Therapy, Regional Hemotherapy Center of the Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
- Oncology, Stem Cell and Cell-Therapy Graduate Program, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Djúlio C. Zanin-Silva
- Center for Cell-Based Therapy, Regional Hemotherapy Center of the Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
- Basic and Applied Immunology Graduate Program, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Kelen C. R. Malmegrim
- Center for Cell-Based Therapy, Regional Hemotherapy Center of the Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
- Department of Clinical, Toxicological and Bromatological Analysis, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - Maria Carolina Oliveira
- Center for Cell-Based Therapy, Regional Hemotherapy Center of the Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
- Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
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Bruera S, Sidanmat H, Molony DA, Mayes MD, Suarez-Almazor ME, Krause K, Lopez-Olivo MA. Stem cell transplantation for systemic sclerosis. Cochrane Database Syst Rev 2022; 7:CD011819. [PMID: 35904231 PMCID: PMC9336163 DOI: 10.1002/14651858.cd011819.pub2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by systemic inflammation, fibrosis, vascular injury, reduced quality of life, and limited treatment options. Autologous hematopoietic stem cell transplantation (HSCT) has emerged as a potential intervention for severe SSc refractory to conventional treatment. OBJECTIVES To assess the benefits and harms of autologous hematopoietic stem cell transplantation for the treatment of systemic sclerosis (specifically, non-selective myeloablative HSCT versus cyclophosphamide; selective myeloablative HSCT versus cyclophosphamide; non-selective non-myeloablative HSCT versus cyclophosphamide). SEARCH METHODS We searched for randomized controlled trials (RCTs) in CENTRAL, MEDLINE, Embase, and trial registries from database insertion to 4 February 2022. SELECTION CRITERIA We included RCTs that compared HSCT to immunomodulators in the treatment of SSc. DATA COLLECTION AND ANALYSIS Two review authors independently selected studies for inclusion, extracted study data, and performed risk of bias and GRADE assessments to assess the certainty of evidence using standard Cochrane methods. MAIN RESULTS We included three RCTs evaluating: non-myeloablative non-selective HSCT (10 participants), non-myeloablative selective HSCT (79 participants), and myeloablative selective HSCT (36 participants). The comparator in all studies was cyclophosphamide (123 participants). The study examining non-myeloablative non-selective HSCT had a high risk of bias given the differences in baseline characteristics between the two arms. The other studies had a high risk of detection bias for participant-reported outcomes. The studies had follow-up periods of one to 4.5 years. Most participants had severe disease, mean age 40 years, and the duration of disease was less than three years. Efficacy No study demonstrated an overall mortality benefit of HSCT when compared to cyclophosphamide. However, non-myeloablative selective HSCT showed overall survival benefits using Kaplan-Meier curves at 10 years and myeloablative selective HSCT at six years. We graded our certainty of evidence as moderate for non-myeloablative selective HSCT and myeloablative selective HSCT. Certainty of evidence was low for non-myeloablative non-selective HSCT. Event-free survival was improved compared to cyclophosphamide with non-myeloablative selective HSCT at 48 months (hazard ratio (HR) 0.34, 95% confidence interval (CI) 0.16 to 0.74; moderate-certainty evidence). There was no improvement with myeloablative selective HSCT at 54 months (HR 0.54 95% CI 0.23 to 1.27; moderate-certainty evidence). The non-myeloablative non-selective HSCT trial did not report event-free survival. There was improvement in functional ability measured by the Health Assessment Questionnaire Disability Index (HAQ-DI, scale from 0 to 3 with 3 being very severe functional impairment) with non-myeloablative selective HSCT after two years with a mean difference (MD) of -0.39 (95% CI -0.72 to -0.06; absolute treatment benefit (ATB) -13%, 95% CI -24% to -2%; relative percent change (RPC) -27%, 95% CI -50% to -4%; low-certainty evidence). Myeloablative selective HSCT demonstrated a risk ratio (RR) for improvement of 3.4 at 54 months (95% CI 1.5 to 7.6; ATB -37%, 95% CI -18% to -57%; RPC -243%, 95% CI -54% to -662%; number needed to treat for an additional beneficial outcome (NNTB) 3, 95% CI 2 to 9; low-certainty evidence). The non-myeloablative non-selective HSCT trial did not report HAQ-DI results. All transplant modalities showed improvement of modified Rodnan skin score (mRSS) (scale from 0 to 51 with the higher number being more severe skin thickness) favoring HSCT over cyclophosphamide. At two years, non-myeloablative selective HSCT showed an MD in mRSS of -11.1 (95% CI -14.9 to -7.3; ATB -22%, 95% CI -29% to -14%; RPC -43%, 95% CI -58% to -28%; moderate-certainty evidence). At 54 months, myeloablative selective HSCT at showed a greater improvement in skin scores than the cyclophosphamide group (RR 1.51, 95% CI 1.06 to 2.13; ATB -27%, 95% CI -6% to -47%; RPC -51%, 95% CI -6% to -113%; moderate-certainty evidence). The NNTB was 4 (95% CI 3 to 18). At one year, for non-myeloablative non-selective HSCT the MD was -16.00 (95% CI -26.5 to -5.5; ATB -31%, 95% CI -52% to -11%; RPC -84%, 95% CI -139% to -29%; low-certainty evidence). No studies reported data on pulmonary arterial hypertension. Adverse events In the non-myeloablative selective HSCT study, there were 51/79 serious adverse events with HSCT and 30/77 with cyclophosphamide (RR 1.7, 95% CI 1.2 to 2.3), with an absolute risk increase of 26% (95% CI 10% to 41%), and a relative percent increase of 66% (95% CI 20% to 129%). The number needed to treat for an additional harmful outcome was 4 (95% CI 3 to 11) (moderate-certainty evidence). In the myeloablative selective HSCT study, there were similar rates of serious adverse events between groups (25/34 with HSCT and 19/37 with cyclophosphamide; RR 1.43, 95% CI 0.99 to 2.08; moderate-certainty evidence). The non-myeloablative non-selective HSCT trial did not clearly report serious adverse events. AUTHORS' CONCLUSIONS Non-myeloablative selective and myeloablative selective HSCT had moderate-certainty evidence for improvement in event-free survival, and skin thicknesscompared to cyclophosphamide. There is also low-certainty evidence that these modalities of HSCT improve physical function. However, non-myeloablative selective HSCT and myeloablative selective HSCT resulted in more serious adverse events than cyclophosphamide; highlighting the need for careful risk-benefit considerations for people considering these HSCTs. Evidence for the efficacy and adverse effects of non-myeloablative non-selective HSCT is limited at this time. Due to evidence provided from one study with high risk of bias, we have low-certainty evidence that non-myeloablative non-selective HSCT improves outcomes in skin scores, forced vital capacity, and safety. Two modalities of HSCT appeared to be a promising treatment option for SSc though there is a high risk of early treatment-related mortality and other adverse events. Additional research is needed to determine the effectiveness and adverse effects of non-myeloablative non-selective HSCT in the treatment of SSc. Also, more studies will be needed to determine how HSCT compares to other treatment options such as mycophenolate mofetil, as cyclophosphamide is no longer the first-line treatment for SSc. Finally, there is a need for a greater understanding of the role of HSCT for people with SSc with significant comorbidities or complications from SSc that were excluded from the trial criteria.
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Affiliation(s)
- Sebastian Bruera
- Department of Internal Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Harish Sidanmat
- Department of General Internal Medicine, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA
| | - Donald A Molony
- Internal Medicine, UT-Houston Health Science Center, Houston, Texas, USA
| | - Maureen D Mayes
- Division of Rheumatology and Clinical Immunogenetics, The University of Texas at Houston Medical School, Houston, Texas, USA
| | - Maria E Suarez-Almazor
- Department of Health Services Research, The University of Texas, MD Anderson Cancer Center, Houston, USA
| | - Kate Krause
- Research Medical Library, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA
| | - Maria Angeles Lopez-Olivo
- Department of Health Services Research, The University of Texas, MD Anderson Cancer Center, Houston, USA
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7
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Boukouaci W, Lansiaux P, Lambert NC, Picard C, Clave E, Cras A, Marjanovic Z, Farge D, Tamouza R. Non-Classical HLA Determinants of the Clinical Response after Autologous Stem Cell Transplantation for Systemic Sclerosis. Int J Mol Sci 2022; 23:ijms23137223. [PMID: 35806227 PMCID: PMC9266677 DOI: 10.3390/ijms23137223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 06/17/2022] [Accepted: 06/27/2022] [Indexed: 12/10/2022] Open
Abstract
Systemic Sclerosis (SSc) is a chronic autoimmune disease with high morbidity and mortality. Autologous Hematopoietic Stem Cell Transplantation (AHSCT) is the best therapeutic option for rapidly progressive SSc, allowing increased survival with regression of skin and lung fibrosis. The immune determinants of the clinical response after AHSCT have yet to be well characterized. In particular, the pivotal role of the Human Leukocyte Antigen (HLA) system is not well understood, including the role of non-classical immuno-modulatory HLA-E and HLA-G molecules in developing tolerance and the role of Natural Killer cells (NK) in the immunomodulation processes. We retrospectively tested whether the genetic and/or circulating expression of the non-classical HLA-E and HLA-G loci, as well as the imputed classical HLA determinants of HLA-E expression, influence the observed clinical response to AHSCT at 12- and 24-month follow-up. In a phenotypically well-defined sample of 46 SSc patients classified as clinical responders or non-responders, we performed HLA genotyping using next-generation sequencing and circulating levels of HLA-G and quantified HLA-E soluble isoforms by ELISA. The -21HLA-B leader peptide dimorphism and the differential expression level of HLA-A and HLA-C alleles were imputed. We observed a strong trend towards better clinical response in HLA-E*01:03 or HLA-G 14bp Del allele carriers, which are known to be associated with high expression of the corresponding molecules. At 12-month post-AHSCT follow-up, higher circulating levels of soluble HLA-E were associated with higher values of modified Rodnan Skin Score (mRSS) (p = 0.0275), a proxy of disease severity. In the non-responder group, the majority of patients carried a double dose of the HLA-B Threonine leader peptide, suggesting a non-efficient inhibitory effect of the HLA-E molecules. We did not find any correlation between the soluble HLA-G levels and the observed clinical response after AHSCT. High imputed expression levels of HLA-C alleles, reflecting more efficient NK cell inhibition, correlated with low values of the mRSS 3 months after AHSCT (p = 0.0087). This first pilot analysis of HLA-E and HLA-G immuno-modulatory molecules suggests that efficient inhibition of NK cells contributes to clinical response after AHSCT for SSc. Further studies are warranted in larger patient cohorts to confirm our results.
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Affiliation(s)
- Wahid Boukouaci
- Translational Neuropsychiatry Laboratory, Institut National de la Santé et de la Recherche Médicale (IN-SERM, U955), Institut Mondor de Recherche Biomédicale, Université Paris Est Creteil, F-94010 Creteil, France;
| | - Pauline Lansiaux
- Unité de Médecine Interne (UF 04): CRMR MATHEC, Maladies Auto-Immunes et Thérapie Cellulaire, Centre de Référence des Maladies Auto-Immunes Systémiques Rares D’ILE-de-France, Hôpital St-Louis, Assistance-Publique Hôpitaux de Paris, F-75010 Paris, France;
- URP-3518: Recherche Clinique en Hématologie, Immunologie et Transplantation, Institut de Recherche Saint-Louis, Université Paris Cité, F-75010 Paris, France
| | - Nathalie C. Lambert
- UMRs 1097 Arthrites Autoimmunes, Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille University, F-13288 Marseille, France;
| | - Christophe Picard
- UMR7268 ADES (Anthropologie Bio-Culturelle, Droit, Ethique et Santé), Université Aix-Marseille, Etablissement Français du Sang, Centre National de la Recherche Scientifique (CNRS), F-13005 Marseille, France;
| | - Emmanuel Clave
- EMiLy (Ecotaxie, Microenvironnement et Developpement Lymphocytaire), Inserm U1160, Institut de Recherche Saint Louis, Université de Paris, F-75010 Paris, France;
| | - Audrey Cras
- Cell Therapy Unit, Saint Louis Hospital, Assistance-Publique Hôpitaux de Paris, F-75010 Paris, France;
- UMR1140, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, F-75006 Paris, France
| | - Zora Marjanovic
- Department of Hematology, Hopital Saint Antoine, F-75012 Paris, France;
| | - Dominique Farge
- URP-3518: Recherche Clinique en Hématologie, Immunologie et Transplantation, Institut de Recherche Saint-Louis, Université Paris Cité, F-75010 Paris, France
- UMRs 1097 Arthrites Autoimmunes, Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille University, F-13288 Marseille, France;
- Department of Medicine, McGill University, Montreal, QC H3A 1A1, Canada
- Correspondence: (D.F.); (R.T.)
| | - Ryad Tamouza
- Translational Neuropsychiatry Laboratory, Institut National de la Santé et de la Recherche Médicale (IN-SERM, U955), Institut Mondor de Recherche Biomédicale, Université Paris Est Creteil, F-94010 Creteil, France;
- Fondation FondaMental, Département Médico-Universitaire de Psychiatrie et d’Addictologie (DMU IMPACT), Fédération Hospitalo-Universitaire de Médecine de Précision en Psychiatrie (FHU ADAPT), Assistance-Publique Hôpitaux de Paris, F-94010 Creteil, France
- Correspondence: (D.F.); (R.T.)
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8
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Moraes DA, Oliveira MC. Life after Autologous Hematopoietic Stem Cell Transplantation for Systemic Sclerosis. J Blood Med 2021; 12:951-964. [PMID: 34785969 PMCID: PMC8590726 DOI: 10.2147/jbm.s338077] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 10/26/2021] [Indexed: 12/29/2022] Open
Abstract
Stem cell transplantation has been investigated as treatment for severe and progressive systemic sclerosis (SSc) for the past 25 years. To date, more than 1000 SSc patients have been transplanted worldwide. Overall and event-free survival have increased over the years, reflecting stricter patient selection criteria and better clinical management strategies. This review addresses long-term outcomes of transplanted SSc patients, considering phase I/II and randomized clinical trials, as well as observational studies and those assessing specific aspects of the disease. Clinical outcomes are discussed comparatively between studies, highlighting advances, drawbacks and controversies in the field. Areas for future development are also discussed.
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Affiliation(s)
- Daniela A Moraes
- Division of Clinical Immunology, Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Maria Carolina Oliveira
- Center for Cell-Based Therapy, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
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9
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Lansiaux P, Loisel S, Castilla-Llorente C, Fontenille C, Kabdani S, Marjanovic Z, Pugnet G, Puyade M, Robert E, Terriou L, Ait Abdallah N, Maria ATJ, Michel L, Tréton X, Yakoub-Agha I, Farge D. [Autologous hematopoietic cells for severe autoimmune diseases: Guidelines of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) for immune monitoring and biobanking]. Bull Cancer 2021; 108:S72-S81. [PMID: 34272057 DOI: 10.1016/j.bulcan.2021.03.020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 02/25/2021] [Accepted: 03/02/2021] [Indexed: 12/29/2022]
Abstract
Autologous hematopoietic cell transplantation (AHCT) is a new treatment option for patients with severe autoimmune diseases (AD), based on the use of intensive or myeloablative chemotherapy to eradicate the pathogenic autoreactive immune cells and to allow the installation of a new and tolerant immune system during immune reconstitution process. Immune reconstitution analysis after AHCT is required for patients clinical follow-up and to further identify biological and immunological markers of the clinical response to develop individualized AHCT protocols. These MATHEC-SFGM-TC good clinical practice guidelines were developed by a multidisciplinary group of experts including members of the french reference center for stem Cell Therapy in Auto-immune Diseases (MATHEC), hematologists from the French speaking Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) and experts in immune monitoring and biobanking. The objectives are to provide practical recommandations for immune monitoring and biobanking of samples in patients with AD undergoing AHCT, for routine care purposes and investigational studies.
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Affiliation(s)
- Pauline Lansiaux
- AP-HP, hôpital Saint-Louis, unité de médecine interne (UF 04): CRMR MATHEC, Maladies auto-immunes et thérapie cellulaire, Centre de Référence des Maladies auto-immunes systémiques Rares d'Ile-de-France MATHEC (FAI2R), 75010 Paris, France; Université de Paris, Institut de recherche Saint-Louis, recherche clinique appliquée à l'hématologie, EA3518, 75010 Paris, France
| | - Séverine Loisel
- CHU de Rennes, établissement français du sang Bretagne, SITI, 35000 Rennes, France
| | - Cristina Castilla-Llorente
- Gustave-Roussy Cancer Center, département d'hématologie, 114, rue Edouard-Vaillant, 94800 Villejuif, France
| | - Claire Fontenille
- Institut Paoli-Calmettes, Association CRYOSTEM, 13009 Marseille, France
| | - Sarah Kabdani
- EFS HFNO site de Lille, unité de thérapie cellulaire, parc Eurasanté, 20, avenue Pierre-Mauroy, 59373 Loos, France
| | - Zora Marjanovic
- AP-HP, hôpital Saint-Antoine, service d'hématologie, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France
| | - Grégory Pugnet
- CHU de Rangueil, service de médecine interne et immunologie clinique, 1, avenue du Professeur Jean-Poulhès, 31059 Toulouse cedex 9, France
| | - Mathieu Puyade
- CHU de Poitiers, service de médecine interne, 2, rue de la Miletrie, 86021 Poitiers, France; CHU de Poitiers, CIC-1402, 2, rue de la Miletrie, 86021 Poitiers, France
| | - Emilie Robert
- Institut Paoli-Calmettes, Association CRYOSTEM, 13009 Marseille, France
| | - Louis Terriou
- Hôpital Claude-Huriez, CHRU Lille, service de médecine interne et immunologie clinique, rue Michel-Polonovski, 59000 Lille, France
| | - Nassim Ait Abdallah
- AP-HP, hôpital Saint-Louis, unité de médecine interne (UF 04): CRMR MATHEC, Maladies auto-immunes et thérapie cellulaire, Centre de Référence des Maladies auto-immunes systémiques Rares d'Ile-de-France MATHEC (FAI2R), 75010 Paris, France; Université de Paris, Institut de recherche Saint-Louis, recherche clinique appliquée à l'hématologie, EA3518, 75010 Paris, France
| | - Alexandre Thibault Jacques Maria
- CHRU de Montpellier, hôpital Saint-Éloi, médecine interne : maladies multi-organiques de l'adulte, Inserm U1183 IRMB, 34295 Montpellier cedex 5, France
| | - Laure Michel
- CHU de Rennes, seervice de neurologie, Rennes, France
| | - Xavier Tréton
- Hôpital Beaujon, université de Paris, service de gastro-entérologie, MICI et Assistance Nutritive, DMU DIGEST, 100, boulevard Leclerc, 92110 Clichy, France
| | | | - Dominique Farge
- AP-HP, hôpital Saint-Louis, unité de médecine interne (UF 04): CRMR MATHEC, Maladies auto-immunes et thérapie cellulaire, Centre de Référence des Maladies auto-immunes systémiques Rares d'Ile-de-France MATHEC (FAI2R), 75010 Paris, France; Université de Paris, Institut de recherche Saint-Louis, recherche clinique appliquée à l'hématologie, EA3518, 75010 Paris, France; McGill University, Department of Medicine, H3A 1A1, Montreal, Canada.
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10
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Hematopoietic Stem Cell Transplantation Improves Functional Outcomes of Systemic Sclerosis Patients. J Clin Rheumatol 2021; 26:S131-S138. [PMID: 31397762 DOI: 10.1097/rhu.0000000000001117] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND/OBJECTIVE We sought to evaluate if autologous hematopoietic stem cell transplantation (AHSCT) influences the functional status of systemic sclerosis (SSc) patients. METHODS From 2014 to 2018, a cohort of 27 SSc patients was assessed before, and at 6 and 12 months after AHSCT for modified Rodnan's skin score (mRSS), mouth opening, hand grip strength, range of motion (ROM), functional ability of upper limbs (DASH questionnaire and Cochin hand function scale-CHFS), 6-minute walk test (6MWT), and quality of life (SF-36 questionnaire). Linear regression models with random effects and Spearman's test were used for statistical analysis. RESULTS At 6 and 12 months after AHSCT, respectively, we observed significant improvement of mRSS (p < 0.01 and p < 0.01), mouth opening (p = 0.02 and p < 0.01), hand function (DASH, p < 0.01 and p < 0.01; CHFS, p < 0.01 and p < 0.01; strength, p < 0.01 and p < 0.01), physical capacity (6MWT, p = 0.02 and p = 0.03) and physical (p < 0.01 and p < 0.01) and mental (ns and p = 0.02) component scores of SF-36. At 12 months after AHSCT, ROM measurements improved (p < 0.05) in five out of six evaluated joints in both hands, compared to baseline. Correlation was significant between physical capacity and quality of life (R = 0.62; p < 0.01), between DASH and quality of life (R = -0.48; p = 0.03), and between skin involvement and wrist ROM measures (dominant hand, R = -0.65, p < 0.01; non-dominant hand, R = -0.59; p < 0.01). CONCLUSIONS AHSCT enhances the functional status of SSc patients in the first year of follow-up, significantly improving hand function, physical capacity and quality of life. These results are interpreted as positive outcomes of AHSCT for SSc.
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11
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Shah A, Spierings J, van Laar JM, Sullivan KM. Re-evaluating inclusion criteria for autologous hematopoietic stem cell transplantation in advanced systemic sclerosis: Three successful cases and review of the literature. JOURNAL OF SCLERODERMA AND RELATED DISORDERS 2021; 6:199-205. [PMID: 35386745 PMCID: PMC8892924 DOI: 10.1177/2397198320985766] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 12/11/2020] [Indexed: 01/22/2024]
Abstract
Systemic sclerosis is a chronic autoimmune disease with a poor prognosis, particularly when a patient has rapidly progressive skin or pulmonary involvement. Autologous hematopoietic stem cell transplant is an emerging treatment for this condition, that has been demonstrated to be more effective than immunosuppressants. Careful selection of patients has reduced the transplant-related mortality and maximized the likelihood of benefit. In this report, we present three cases of successful autologous hematopoietic stem cell transplant in patients who would not have met inclusion criteria for entrance into the completed hematopoietic stem cell transplant. After >18 months of follow-up, three patients had clinically significant benefit in terms of skin tightening and pulmonary function tests. Future studies of hematopoietic stem cell transplant in systemic sclerosis may aim to carefully liberalize inclusion criteria to include patients who may not have otherwise been treated while still maintaining an acceptable safety profile.
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Affiliation(s)
- Ankoor Shah
- Division of Rheumatology, Duke University, Durham, NC, USA
| | - J Spierings
- Department of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - JM van Laar
- Department of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands
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12
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Urbain F, Labeyrie C, Castilla-Llorente C, Cintas P, Puma A, Maubeuge N, Puyade M, Farge D. [Autologous hematopoietic stem cell transplantation for chronic inflammatory demyelinating polyneuropathy]. Rev Med Interne 2021; 42:639-649. [PMID: 33773849 DOI: 10.1016/j.revmed.2021.03.008] [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: 09/01/2020] [Revised: 02/02/2021] [Accepted: 03/13/2021] [Indexed: 10/21/2022]
Abstract
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a dysimmune neuropathy with sensory and/or motor symptoms due to destruction of the myelin sheat secondary to an auto-immune attack. A quarter to a third of patients do not respond to immunomodulatory first line recommended therapies. No second line treatment has shown its effectiveness with a sufficient level of evidence. Autologous hematopoietic stem cell transplantation (AHSCT) is a promising therapy for autoimmune disease, especially for CIDP in recent works. We present in this article an update on the diagnosis of CIDP, its conventional treatments as well as the results of AHSCT in this indication, which was the subject of French recommendations under the aegis of the SFGMTC and neuromuscular disease french faculty (FILNEMUS) as a third line therapy after failure of two first-line and one second-line treatments.
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Affiliation(s)
- F Urbain
- Assistance Publique-Hôpitaux de Paris, Université Paris-Saclay, service de medecine interne, groupe hospitalier universitaire Paris Sud, hôpital Bicêtre, 94275 Le Kremlin-Bicêtre cedex, France.
| | - C Labeyrie
- Assistance Publique-Hôpitaux de Paris, centre de reference maladies rares neuropathies amyloïdes familiales et autres neuropathies peripheriques rares, service de neurologie, groupe hospitalier universitaire Paris Sud, hôpital Bicêtre, 94275 Le Kremlin-Bicêtre cedex, France
| | - C Castilla-Llorente
- Institut Gustave-Roussy, service d'hématologie, 114, rue Édouard-Vaillant, 94800 Villejuif, France
| | - P Cintas
- Explorations neurophysiologiques, centre SLA, centre de référence de pathologie neuromusculaire, CHU Toulouse, hôpital Pierre-Paul-Riquet, 31059 Toulouse Cedex, France
| | - A Puma
- Maladies du systeme nerveux peripherique et du muscle, Centre SLA, hôpital Pasteur 2-Zone C, CS 51069, 06001 Nice cedex 1, France
| | - N Maubeuge
- CHU de Poitiers, service de neurologie, 2, rue de la Milétrie, 86021 Poitiers cedex, France
| | - M Puyade
- CHU de Poitiers, service de médecine interne et maladies infectieuses, 2, rue de la Milétrie, 86021 Poitiers cedex, France; CHU de Poitiers, CIC-1402, 2, rue de la Milétrie, 86021 Poitiers cedex, France
| | - D Farge
- Unité de médecine interne, maladies auto-immunes et pathologie vasculaire UF04, Centre de référence des maladies auto-immunes systémiques rares d'Île-de-France MATHEC Hôpital Saint-Louis, UF04, Filière 'FAI2R', 1, avenue Claude-Vellefaux, 75475 Paris, France; Université de Paris, EA 3518, Paris, France; Département de Médecine, Université McGill, Montreal, QC, Canada
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13
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Connolly MK. Systemic sclerosis (scleroderma): remaining challenges. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:438. [PMID: 33842659 PMCID: PMC8033370 DOI: 10.21037/atm-20-5449] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Despite progress in treating internal organ involvement in systemic sclerosis (scleroderma) (SSc), such as pulmonary disease, effective treatments for the hallmark of the disease, cutaneous fibrosis, remain elusive. None of the disease-modifying antirheumatic drugs (DMARDS) have shown proven efficacy for SSc skin fibrosis, and there remain no FDA-approved medications, all of which are off-label, for cutaneous fibrosis in SSc. This review article will briefly summarize conventional therapies, biologics and hematopoietic stem cell transplants and select ongoing clinical trials in SSc. The gold standard for measuring skin fibrosis in SSc is the modified Rodnan skin score (MRSSS). This is a validated test that measures skin thickness (0 to 3) at 17 locations for a total score of 51. Improvements in skin score over time are used in clinical trials to quantitate skin fibrosis. Although recording the Rodnan skin score is technically straightforward, requiring no special equipment, and noninvasive, the fluctuating natural history of the disease includes improvement over time without interventions, rendering meaningful trials difficult to assess. Understanding of the basic molecular mechanisms driving pathologic fibrosis in SSc remains lacking, and underpins the often empiric nature and likely the lack of efficacy of many therapeutics that have been tried. Although repeated skin biopsies might be a more precise way to follow disease progression and regression, this is necessarily invasive and requires special tools. Here, this review will look at conventional therapies, biologics, autologous hematopoietic stem cell transplantation, and catalog some of the ongoing clinical trials in SSc with a focus on cutaneous fibrosis.
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Affiliation(s)
- Mary Karin Connolly
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA
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14
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Henrique-Neto Á, Vasconcelos MYK, Dias JBE, de Moraes DA, Gonçalves MS, Zanin-Silva DC, Zucoloto TG, de Oliveira MDFC, Dotoli GM, Weffort LF, Leopoldo VC, Oliveira MC. Hematopoietic stem cell transplantation for systemic sclerosis: Brazilian experience. Adv Rheumatol 2021; 61:9. [PMID: 33549135 DOI: 10.1186/s42358-021-00166-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 01/26/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND In the past 20 years, hematopoietic stem cell transplantation (HSCT) has been investigated as treatment for systemic sclerosis (SSc). The goal of HSCT is to eradicate the autoreactive immune system, which is replaced by a new immune repertoire with long-lasting regulation and tolerance to autoantigens. Here, we describe the clinical outcomes of severe and refractory SSc patients that underwent HSCT at a single Brazilian center. PATIENTS AND METHODS This is a longitudinal and retrospective study, including 70 adult SSc patients, with an established diagnosis of SSc, and who underwent autologous HSCT from 2009 to 2016. The procedure included harvesting and cryopreservation of autologous hematopoietic progenitor cells, followed by administration of an immunoablative regimen and subsequent infusion of the previously collected cells. Patients were evaluated immediately before transplantation, at 6 months and then yearly until at least 5-years of post-transplantation follow-up. At each evaluation time point, patients underwent clinical examination, including modified Rodnan's skin score (mRSS) assessment, echocardiography, high-resolution computed tomography of the lungs and pulmonary function. RESULTS Median (range) age was 35.9 (19-59), with 57 (81.4%) female and median (range) non-Raynaud's disease duration of 2 (1-7) years. Before transplantation, 96% of the patients had diffuse skin involvement, 84.2%, interstitial lung disease and 67%, positive anti-topoisomerase I antibodies. Skin involvement significantly improved, with a decline in mRSS at all post-transplantation time points until at least 5-years of follow-up. When patients with pre-HSCT interstitial lung disease were analyzed, there was an improvement in pulmonary function (forced vital capacity and diffusing capacity of lung for carbon monoxide) over the 5-year follow-up. Overall survival was 81% and progression-free survival was 70.5% at 8-years after HSCT. Three patients died due to transplant-related toxicity, 9 patients died over follow-up due to disease reactivation and one patient died due to thrombotic thrombocytopenic purpura. CONCLUSIONS Autologous hematopoietic progenitor cell transplantation improves skin and interstitial lung involvement. These results are in line with the international experience and support HSCT as a viable therapeutic alternative for patients with severe and progressive systemic sclerosis.
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Affiliation(s)
- Álvaro Henrique-Neto
- Graduate Program in Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Marianna Yumi Kawashima Vasconcelos
- Graduate Program in Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.,Center for Cell-Based Therapy, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Juliana Bernardes Elias Dias
- Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Daniela Aparecida de Moraes
- Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Maynara Santana Gonçalves
- Center for Cell-Based Therapy, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.,Graduate Program in Oncology, Stem Cells and Cell Therapy, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Djúlio César Zanin-Silva
- Center for Cell-Based Therapy, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.,Graduate Program in Basic and Applied Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Talita Graminha Zucoloto
- Graduate Program in Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.,Center for Cell-Based Therapy, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.,Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Marília de Fátima Cirioli de Oliveira
- Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.,Ribeirão Preto School of Nursing, University of São Paulo, Ribeirão Preto, Brazil
| | - Giuliana Martinelli Dotoli
- Graduate Program in Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.,Center for Cell-Based Therapy, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Luiz Fernando Weffort
- Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Vanessa Cristina Leopoldo
- Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.,Ribeirão Preto School of Nursing, University of São Paulo, Ribeirão Preto, Brazil
| | - Maria Carolina Oliveira
- Center for Cell-Based Therapy, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil. .,Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Avenida dos Bandeirantes 3900, Ribeirão Preto, SP, 14048-900, Brazil.
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15
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Farge D, Ait Abdallah N, Marjanovic Z, Del Papa N. Autologous stem cell transplantation in scleroderma. Presse Med 2021; 50:104065. [PMID: 33548374 DOI: 10.1016/j.lpm.2021.104065] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 01/29/2021] [Indexed: 12/29/2022] Open
Abstract
Patients with severe rapidly progressive systemic sclerosis (SSc) have a poor prognosis. Standard immunosuppressive therapies may have modest effects on stabilizing disease, but they fail to improve overall survival. Hematopoietic stem cell transplant (HSCT) is the first treatment to induce disease-modifying therapeutic benefits in rapidly progressive SSc patients. HSCT in rapidly progressive SSc can induce regression of fibrosis in skin and lung, and increase survival. Initially, HSCT was associated with high treatment-related mortality rates. Improvements in patient screening, a better understanding of the risks associated with different treatment regimens, and centre experience have improved the AHSCT safety profile for patients with scleroderma.
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Affiliation(s)
- Dominique Farge
- Assistance Publique-Hôpitaux de Paris, Saint-Louis Hospital, Internal Medicine (UF04), MATHEC, Centre of reference for rare systemic autoimmune diseases (FAI2R); Université de Paris, EA 3518, Paris, France; McGill university, department of medicine, Montreal, QC, Canada.
| | - Nassim Ait Abdallah
- Assistance Publique-Hôpitaux de Paris, Saint-Louis Hospital, Internal Medicine (UF04), MATHEC, Centre of reference for rare systemic autoimmune diseases (FAI2R); Université de Paris, EA 3518, Paris, France
| | - Zora Marjanovic
- Saint-Antoine hospital, department of haematology, Paris, France
| | - Nicoletta Del Papa
- Scleroderma clinic, Ospedale G. Pini, University of Milan, department of rheumatology, Milano, Italy
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16
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Henes J, Oliveira MC, Labopin M, Badoglio M, Scherer HU, Del Papa N, Daikeler T, Schmalzing M, Schroers R, Martin T, Pugnet G, Simoes B, Michonneau D, Marijt EWA, Lioure B, Olivier Bay J, Snowden JA, Rovira M, Huynh A, Onida F, Kanz L, Marjanovic Z, Farge D. Autologous stem cell transplantation for progressive systemic sclerosis: a prospective non-interventional study from the European Society for Blood and Marrow Transplantation Autoimmune Disease Working Party. Haematologica 2021; 106:375-383. [PMID: 31949011 PMCID: PMC7849556 DOI: 10.3324/haematol.2019.230128] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Accepted: 01/09/2020] [Indexed: 12/29/2022] Open
Abstract
Three randomized controlled trials in early severe systemic sclerosis demonstrated that autologous hematopoietic stem cell transplantation was superior to standard cyclophosphamide therapy. This European Society for Blood and Marrow Transplantation multicenter, prospective, non-interventional study was designed to further decipher efficacy and safety of this procedure for severe systemic sclerosis patients in real-life practice and to search for prognostic factors. All consecutive adult patients with systemic sclerosis undergoing a first autologous hematopoietic stem cell transplant between December 2012 and February 2016 were prospectively included in the study. The primary endpoint was progression-free survival. Secondary endpoints were overall survival, non-relapse mortality, response and incidence of progression. Eighty patients with systemic sclerosis were included. The median duration of the follow-up was 24 (range, 6-57) months after stem cell transplantation using cyclophosphamide plus antithymocyte globulin conditioning for all, with CD34+ selection in 35 patients. At 2 years, the progression- free survival rate was 81.8%, the overall survival rate was 90%, the response rate was 88.7% and the incidence of progression was 11.9%. The 100-day non-relapse mortality rate was 6.25% (n=5) with four deaths from cardiac events, including three due to cyclophosphamide toxicity. Modified Rodnan skin score and forced vital capacity improved with time (P<0.001). By multivariate analysis, baseline skin score >24 and older age at transplantation were associated with lower progression-free survival (hazard ratios 3.32 and 1.77, respectively). CD34+-cell selection was associated with better response (hazard ratio 0.46). This study confirms the efficacy of autologous stem cell transplantation, using nonmyeloablative conditioning, in real-life practice for severe systemic sclerosis. Careful cardio-pulmonary assessment to identify organ involvement at the time of the patient’s referral, reduced cyclophosphamide doses and CD34+-cell selection may improve outcomes. The study was registered at ClinicalTrials.gov: NCT02516124.
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Affiliation(s)
- Joerg Henes
- University Hospital Tuebingen; Intenal Medicine II, Tuebingen, Germany
| | | | - Myriam Labopin
- Saint Antoine Hospital, Université Pierre et Marie Curie, Paris, France
| | | | - Hans Ulrich Scherer
- Leiden University Medical Center, Department of Rheumatology; Leiden, Netherlands
| | - Nicoletta Del Papa
- Scleroderma Clinic, Osp. G. Pini, Department of Rheumatology, Milan, Italy
| | - Thomas Daikeler
- University and University Hospital of Basel, Department of Rheumatology, Basel, Switzerland
| | - Marc Schmalzing
- University Hospital of Wuerzburg, Department of Rheumatology/Immunology, Wuerzburg, Germany
| | | | - Thierry Martin
- Service de Medecine Interne et Immunologie Clinique, Hopitaux Universitaires de Strasbourg, France
| | - Gregory Pugnet
- CHU de Toulouse, Hopital Purpan, Service de Medecine Interne, Toulouse, France
| | - Belinda Simoes
- Dept. of Hematology, Ribeirão Preto Medical School, University of São Paulo, Brazil
| | - David Michonneau
- Dept. of Hematology, Hopital Saint Louis and Université Paris 7, Denis Diderot, Paris, France
| | - Erik W A Marijt
- Leiden University Medical Center, Department of Hematology, Leiden, Netherlands
| | - Bruno Lioure
- Strasbourg University Hospital, Department of Hematology, Strasbourg, France
| | | | - John A Snowden
- Dept. of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Montserrat Rovira
- Department of Hematology, Hospital Clínic of Barcelona, Barcelona, Spain
| | - Anne Huynh
- UCT Oncopole, Department of Haematology, Toulouse, France
| | - Francesco Onida
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milano Italy
| | - Lothar Kanz
- University Hospital Tuebingen, Department of Internal Medicine II, Tuebingen, Germany
| | - Zora Marjanovic
- Saint Antoine Hospital, Department of Haematology, Paris, France
| | - Dominique Farge
- Assistance Publique-Hopitaux de Paris, Saint-Louis Hospital, Paris, France
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17
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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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18
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Haematopoietic stem cell transplantation in systemic sclerosis: Challenges and perspectives. Autoimmun Rev 2020; 19:102662. [PMID: 32942028 DOI: 10.1016/j.autrev.2020.102662] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 04/07/2020] [Indexed: 12/12/2022]
Abstract
Systemic Sclerosis is chronic progressive autoimmune disease, characterised by microangiopathy and fibrosis. Due to disease heterogeneity, in terms of extent, severity, and rate of progression, optimal therapeutic interventions are still lacking. Haematopoietic stem cells may be a new therapeutic option in this disease and, although the results of the first trials are encouraging, several issues remain to be addressed. On these bases, the stem cells transplantation is an area of active investigation, and an overview of the current available literature may help to define the role of this therapeutic strategy. Although the promising results, some unmet needs remain, including the transplantation protocols and their effects on immune system, the selection of the ideal patient and the pre-transplant cardiopulmonary evaluations. An improvement in these fields will allow us to optimize the haematopoietic stem cell therapies in SSc.
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19
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Maltez N, Puyade M, Wang M, Lansiaux P, Marjanovic Z, Charles C, Steele R, Baron M, Colmegna I, Hudson M, Farge D. Association of Autologous Hematopoietic Stem Cell Transplantation in Systemic Sclerosis With Marked Improvement in Health-Related Quality of Life. Arthritis Rheumatol 2020; 73:305-314. [PMID: 32909693 DOI: 10.1002/art.41519] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 08/18/2020] [Accepted: 09/03/2020] [Indexed: 12/17/2022]
Abstract
OBJECTIVE To quantify the magnitude, domains, and duration of change in health-related quality of life (HRQoL) in patients with systemic sclerosis (SSc) who underwent autologous hematopoietic stem cell transplantation (HSCT) as compared to SSc patients with similar characteristics who did not undergo autologous HSCT. METHODS The study was designed as a retrospective study comparing SSc patients who underwent autologous HSCT and SSc patients who met the criteria for transplantation but were treated with conventional care. Outcomes included scores on the 36-item Short Form (SF-36) health survey and the Health Assessment Questionnaire (HAQ) and its disease-specific symptom scales. Differences in scores between the groups were compared using linear models, adjusting for baseline scores and inverse probability of treatment and censoring weights. RESULTS In total, 41 SSc patients who underwent autologous HSCT and 65 SSc patients treated with conventional care were compared. In marginal linear weighted models, the SF-36 physical component summary score was a mean ± SEM 7.02 ± 1.94 points higher at the first annual visit (P = 0.001) and 14.40 ± 6.16 points higher at the seventh annual visit (P = 0.03) in patients treated with autologous HSCT compared to the conventional care group. HAQ scores were significantly better in the autologous HSCT group compared to the conventional care group during follow-up (mean ± SEM difference from baseline -0.57 ± 0.13 [P < 0.001] at the first annual visit and -0.94 ± 0.49 [P = 0.07] at the seventh annual visit). There were no differences in the SF-36 mental component summary scores between the 2 groups either at baseline or during follow-up. CONCLUSION This study provides robust complementary HRQoL data, including overall and event-free survival data, to expand on the standard repertoire of biomedical variables, thus potentially supporting the physical benefits of autologous HSCT in patients with SSc.
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Affiliation(s)
| | | | - Mianbo Wang
- Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada
| | - Pauline Lansiaux
- Centre de Référence des Maladies Auto-Immunes Systémiques Rares d'Ile-de-France, AP-HP, Hôpital St. Louis, Université de Paris, Institut de Recherche St. Louis, EA 3518, Paris, France
| | | | - Catney Charles
- Centre de Référence des Maladies Auto-Immunes Systémiques Rares d'Ile-de-France, AP-HP, Hôpital St. Louis, Université de Paris, Institut de Recherche St. Louis, EA 3518, Paris, France
| | | | - Murray Baron
- Jewish General Hospital and McGill University Health Center, Montreal, Quebec, Canada
| | - Ines Colmegna
- Jewish General Hospital and McGill University Health Center, Montreal, Quebec, Canada
| | - Marie Hudson
- Lady Davis Institute, Jewish General Hospital, and McGill University, Montreal, Quebec, Canada
| | - Dominique Farge
- Centre de Référence des Maladies Auto-Immunes Systémiques Rares d'Ile-de-France, AP-HP, Hôpital St. Louis, Université de Paris, Institut de Recherche St. Louis, EA 3518, Hôpital St. Antoine, Paris, France, and McGill University, Montreal, Quebec, Canada
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20
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Puyade M, Maltez N, Lansiaux P, Pugnet G, Roblot P, Colmegna I, Hudson M, Farge D. Health-related quality of life in systemic sclerosis before and after autologous haematopoietic stem cell transplant-a systematic review. Rheumatology (Oxford) 2020; 59:779-789. [PMID: 31504944 DOI: 10.1093/rheumatology/kez300] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 06/10/2019] [Indexed: 12/29/2022] Open
Abstract
OBJECTIVES In severe rapidly progressive SSc, autologous haematopoietic stem cell transplantation (AHSCT) allows significant improvements in overall and event-free survival. We undertook this study to identify, appraise and synthesize the evidence on health-related quality of life (HRQoL) before and after AHSCT for SSc. METHODS We performed a systematic review of the literature, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, in PubMed and ScienceDirect from database inception to 1 February 2019. All articles with original HRQoL data were selected. RESULTS The search identified 1080 articles, of which 8 were selected: 3 unblinded randomized controlled trials [American Scleroderma Stem Cell versus Immune Suppression Trial (ASSIST), Autologous Stem Cell Transplantation International Scleroderma, Scleroderma: Cyclophosphamide or Transplantation), 3 uncontrolled phase I or II trials and 2 cohort studies. HRQoL data from 289 SSc patients treated with AHSCT and 125 treated with intravenous CYC as a comparator with median 1.25-4.5 years follow-up were included. HRQoL was evaluated with the HAQ Disability Index (HAQ-DI; 275 patients), the 36-item Short Form Health Survey (SF-36; 249 patients) and the European Quality of Life 5-Dimensions questionnaire (EQ-5D; 138 patients). The quality of the studies was moderate to low. AHSCT was associated with significant improvement in the HAQ-DI (P = 0.02-<0.001), SF-36 Physical Component Summary score (P = 0.02-<0.0001) and EQ-5D index-based utility score (P < 0.001). The SF-36 Mental Component Summary score improved in the ASSIST (n = 19) and one small retrospective cohort (n = 30 patients, P = 0.005) but did not improve significantly in 2 randomized controlled trials (n = 200 patients, P = 0.1-0.91). CONCLUSION AHSCT in severe SSc patients is associated with significant and durable improvement in physical HRQoL.
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Affiliation(s)
- Mathieu Puyade
- Centre Hospitalier Universitaire de Poitiers, Service de Médecine Interne, Maladies infectieuses, France.,Centre Hospitalier Universitaire de Poitiers, CIC1402, Poitiers, France
| | | | - Pauline Lansiaux
- Unité de Médecine Interne: Maladies Auto-immunes et Pathologie Vasculaire (UF 04), Centre de Référence des Maladies auto-immunes systémiques Rares d'Ile-de-France, AP-HP, Hôpital St-Louis, Saint Louis.,Université de Paris, IRSL, Recherche clinique appliquée à l'hématologie, EA 3518, F-75010 Paris
| | - Grégory Pugnet
- CHU de Toulouse, Hôpital Purpan, Service de Médecine Interne, France.,CHU de Toulouse, CIC 1436 module Biothérapie, Toulouse, France
| | - Pascal Roblot
- Centre Hospitalier Universitaire de Poitiers, Service de Médecine Interne, Maladies infectieuses, France.,Université de Poitiers, Poitiers, France
| | - Ines Colmegna
- Research Institute of the McGill University Health Center, Montreal, Canada.,Department of Medicine, McGill University, Montreal, Canada
| | - Marie Hudson
- Department of Medicine, McGill University, Montreal, Canada.,Jewish General Hospital, Lady Davis Institute, Montreal, Canada
| | - Dominique Farge
- Unité de Médecine Interne: Maladies Auto-immunes et Pathologie Vasculaire (UF 04), Centre de Référence des Maladies auto-immunes systémiques Rares d'Ile-de-France, AP-HP, Hôpital St-Louis, Saint Louis.,Université de Paris, IRSL, Recherche clinique appliquée à l'hématologie, EA 3518, F-75010 Paris.,Department of Medicine, McGill University, Montreal, Canada
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21
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Maehara T, Kaneko N, Perugino CA, Mattoo H, Kers, J, Allard-Chamard H, Mahajan VS, Liu H, Murphy SJ, Ghebremichael M, Fox D, Payne AS, Lafyatis R, Stone JH, Khanna D, Pillai S. Cytotoxic CD4+ T lymphocytes may induce endothelial cell apoptosis in systemic sclerosis. J Clin Invest 2020; 130:2451-2464. [PMID: 31990684 PMCID: PMC7190971 DOI: 10.1172/jci131700] [Citation(s) in RCA: 129] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 01/23/2020] [Indexed: 12/18/2022] Open
Abstract
Systemic sclerosis (SSc) is an autoimmune fibrotic disease whose pathogenesis is poorly understood and lacks effective therapies. We undertook quantitative analyses of T cell infiltrates in the skin of 35 untreated patients with early diffuse SSc and here show that CD4+ cytotoxic T cells and CD8+ T cells contribute prominently to these infiltrates. We also observed an accumulation of apoptotic cells in SSc tissues, suggesting that recurring cell death may contribute to tissue damage and remodeling in this fibrotic disease. HLA-DR-expressing endothelial cells were frequent targets of apoptosis in SSc, consistent with the prominent vasculopathy seen in patients with this disease. A circulating effector population of cytotoxic CD4+ T cells, which exhibited signatures of enhanced metabolic activity, was clonally expanded in patients with systemic sclerosis. These data suggest that cytotoxic T cells may induce the apoptotic death of endothelial and other cells in systemic sclerosis. Cell loss driven by immune cells may be followed by overly exuberant tissue repair processes that lead to fibrosis and tissue dysfunction.
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Affiliation(s)
- Takashi Maehara
- Ragon Institute, Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, USA
- Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Naoki Kaneko
- Ragon Institute, Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, USA
- Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan
| | - Cory A. Perugino
- Ragon Institute, Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, USA
- Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Hamid Mattoo
- Ragon Institute, Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, USA
- Immunology and Inflammation Therapeutic Area, Sanofi, Cambridge Massachusetts, USA
| | - Jesper Kers,
- Ragon Institute, Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, USA
- Amsterdam Infection & Immunity Institute (AI&II) and
- Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centers, and
- Van ‘t Hoff Institute for Molecular Sciences (HIMS), University of Amsterdam, Amsterdam, Netherlands
| | - Hugues Allard-Chamard
- Ragon Institute, Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, USA
- Division of Rheumatology, Faculté de médecine et des sciences de la santé, Université de Sherbrooke et Centre de Recherche Clinique Étienne-Le Bel, Sherbrooke, Québec, Canada
| | - Vinay S. Mahajan
- Ragon Institute, Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, USA
- Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Hang Liu
- Ragon Institute, Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, USA
- Department of Rheumatology and Immunology, First Affiliated Hospital of China, Shenyang, China
| | - Samuel J.H. Murphy
- Ragon Institute, Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, USA
| | - Musie Ghebremichael
- Ragon Institute, Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, USA
| | - David Fox
- Division of Rheumatology, Medical School, University of Michigan, Ann Arbor, Michigan, USA
| | - Aimee S. Payne
- Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Robert Lafyatis
- Division of Rheumatology and Clinical Immunology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - John H. Stone
- Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Dinesh Khanna
- Division of Rheumatology, Medical School, University of Michigan, Ann Arbor, Michigan, USA
| | - Shiv Pillai
- Ragon Institute, Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, USA
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22
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Immune rebound associates with a favorable clinical response to autologous HSCT in systemic sclerosis patients. Blood Adv 2019; 2:126-141. [PMID: 29365321 DOI: 10.1182/bloodadvances.2017011072] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Accepted: 11/18/2017] [Indexed: 02/06/2023] Open
Abstract
To evaluate the immunological mechanisms associated with clinical outcomes after autologous hematopoietic stem cell transplantation (AHSCT), focusing on regulatory T- (Treg) and B- (Breg) cell immune reconstitution, 31 systemic sclerosis (SSc) patients underwent simultaneous clinical and immunological evaluations over 36-month posttransplantation follow-up. Patients were retrospectively grouped into responders (n = 25) and nonresponders (n = 6), according to clinical response after AHSCT. Thymic function and B-cell neogenesis were respectively assessed by quantification of DNA excision circles generated during T- and B-cell receptor rearrangements. At the 1-year post-AHSCT evaluation of the total set of transplanted SSc patients, thymic rebound led to renewal of the immune system, with higher T-cell receptor (TCR) diversity, positive correlation between recent thymic emigrant and Treg counts, and higher expression of CTLA-4 and GITR on Tregs, when compared with pretransplant levels. In parallel, increased bone marrow output of newly generated naive B-cells, starting at 6 months after AHSCT, renovated the B-cell populations in peripheral blood. At 6 and 12 months after AHSCT, Bregs increased and produced higher interleukin-10 levels than before transplant. When the nonresponder patients were evaluated separately, Treg and Breg counts did not increase after AHSCT, and high TCR repertoire overlap between pre- and posttransplant periods indicated maintenance of underlying disease mechanisms. These data suggest that clinical improvement of SSc patients is related to increased counts of newly generated Tregs and Bregs after AHSCT as a result of coordinated thymic and bone marrow rebound.
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23
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Autologous haematopoietic stem cell transplantation (AHSCT) in autoimmune disease adult patients in France: analysis of the long-term outcome from the French Society for Bone Marrow Transplantation and Cellular Therapy (SFGM-TC). Clin Rheumatol 2019; 38:1501-1511. [DOI: 10.1007/s10067-019-04435-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 12/22/2018] [Accepted: 01/04/2019] [Indexed: 12/29/2022]
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24
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Alexander T, Farge D, Badoglio M, Lindsay JO, Muraro PA, Snowden JA. Hematopoietic stem cell therapy for autoimmune diseases - Clinical experience and mechanisms. J Autoimmun 2018; 92:35-46. [PMID: 29934135 DOI: 10.1016/j.jaut.2018.06.002] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 06/07/2018] [Accepted: 06/08/2018] [Indexed: 12/13/2022]
Abstract
With accumulating evidence and improved outcomes along with recognition that modern biological therapies are not universally effective, require chronic administration and have high acquisition costs, hematopoietic stem cell transplantation (HSCT) has become an emerging direction for cell therapy in autoimmune diseases (ADs). The goal of this therapy is to induce medication-free remissions by resetting the immune system into a naïve and self-tolerant state through eradication of the autoreactive immunologic memory and profound re-configuration of the immune system induced by the transplant procedure. Safety of HSCT has generally improved by implementing internal quality management and external accreditation. Inter-disciplinary guidelines for patient selection, transplant technique and supportive care along with greater center experience should optimize safe and appropriate delivery of HSCT in specific ADs. In this review, we discuss the current role and future perspectives of HSCT in AD, focusing on recent published clinical and scientific studies and recommendations in the field.
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Affiliation(s)
- Tobias Alexander
- Department of Rheumatology and Clinical Immunology, Charité - University Medicine Berlin, Germany.
| | - Dominique Farge
- Unité de Médecine Interne, Maladies Auto-immunes et Pathologie Vasculaire (UF 04), Hôpital St-Louis, AP-HP, 1 avenue Claude Vellefaux, 75010 Paris, Université Denis Diderot, France; Centre de Référence des Maladies auto-immunes systémiques Rares d'Ile-de-France (site constitutif), Filière FAI2R, France
| | - Manuela Badoglio
- EBMT Paris Study Office / CEREST-TC, Department of Haematology, Saint Antoine Hospital, INSERM UMR 938, Université Pierre et Marie Curie, Paris, France
| | - James O Lindsay
- The Royal London Hospital, Barts Health NHS Trust, London, E1 1BB UK; Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, E1 2AT, UK
| | - Paolo A Muraro
- Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK
| | - John A Snowden
- Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, S10 2JF, UK
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25
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Eyraud A, Scouppe L, Barnetche T, Forcade E, Lazaro E, Duffau P, Richez C, Seneschal J, Truchetet ME. Efficacy and safety of autologous haematopoietic stem cell transplantation in systemic sclerosis: a systematic review of the literature. Br J Dermatol 2018; 178:650-658. [PMID: 28906550 DOI: 10.1111/bjd.15993] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/05/2017] [Indexed: 12/21/2022]
Abstract
We aimed to assess the efficacy of autologous haematopoietic stem cell transplantation (HSCT) for skin sclerosis (SSc) and lung function in SSc. We performed a systematic literature review in the PubMed and Scopus databases from the earliest records to March 2016. We assessed study quality using the Cochrane tool for randomized studies, the Newcastle-Ottawa Scale for controlled cohort studies and an 18-item quality-appraisal checklist for case series. The primary outcome was the improvement of skin thickening using the modified Rodnan Skin Score (mRSS). The secondary outcome was efficacy on lung function, using diffusing capacity of the lungs for carbon monoxide and forced vital capacity (FVC). The safety of the procedure was evaluated. The literature search identified 431 citations. There were 38 studies involving a total of 344 patients who fulfilled our inclusion criteria. No meta-analysis was performed due to a high heterogeneity. There was a significant improvement in mRSS in the majority of the reports (P < 0·05), and the results were sustained for up to 8 years after autologous HSCT. The randomized studies and the four cohort studies each showed a slight but statistically significant improvement in FVC at 1 or 2 years. The treatment-related mortality calculated by pooling patients of 35 studies (336 patients with a follow-up up to 146 months) was 8·3% after autologous HSCT and 1% in cyclophosphamide-treated groups. Despite heterogeneity among the studies, we determined that autologous HSCT significantly improved cutaneous fibrosis and slightly improved FVC. Safety of autologous HSCT is acceptable given the severity of the disease. This systematic review was registered on PROSPERO, number CRD42016027951.
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Affiliation(s)
- A Eyraud
- Department of Dermatology, Hôpital Saint-André, CHU de Bordeaux, Bordeaux, France
| | - L Scouppe
- Department of Rheumatology, Hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France
| | - T Barnetche
- Department of Rheumatology, Hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France
| | - E Forcade
- Department of Hematology, Hôpital Haut-Levêque, CHU de Bordeaux, Bordeaux, France.,Immunology Laboratory, ImmunoConCEpt, UMR CNRS 5164, Université de Bordeaux, 33076, Bordeaux, France
| | - E Lazaro
- Immunology Laboratory, ImmunoConCEpt, UMR CNRS 5164, Université de Bordeaux, 33076, Bordeaux, France.,Department of Internal Medicine, Hôpital Haut-Levêque, CHU de Bordeaux, Bordeaux, France
| | - P Duffau
- Immunology Laboratory, ImmunoConCEpt, UMR CNRS 5164, Université de Bordeaux, 33076, Bordeaux, France.,Department of Internal Medicine, Hôpital Saint-André, CHU de Bordeaux, Bordeaux, France
| | - C Richez
- Department of Rheumatology, Hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France.,Immunology Laboratory, ImmunoConCEpt, UMR CNRS 5164, Université de Bordeaux, 33076, Bordeaux, France
| | - J Seneschal
- Department of Dermatology, Hôpital Saint-André, CHU de Bordeaux, Bordeaux, France.,Department of Dermatology and Paediatric Dermatology, INSERM U1035 Immuno-dermatology ATIP-AVENIR, Université de Bordeaux, 33076, Bordeaux, France
| | - M-E Truchetet
- Department of Rheumatology, Hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France.,Immunology Laboratory, ImmunoConCEpt, UMR CNRS 5164, Université de Bordeaux, 33076, Bordeaux, France
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26
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Shouval R, Furie N, Raanani P, Nagler A, Gafter-Gvili A. Autologous Hematopoietic Stem Cell Transplantation for Systemic Sclerosis: A Systematic Review and Meta-Analysis. Biol Blood Marrow Transplant 2018; 24:937-944. [PMID: 29374527 DOI: 10.1016/j.bbmt.2018.01.020] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Accepted: 01/17/2018] [Indexed: 12/29/2022]
Abstract
Autologous hematopoietic stem cell transplantation (AHSCT) has been proposed as a therapeutic modality for severe systemic sclerosis (SSc). We set out to systematically review and meta-analyze the efficacy and safety of AHSCT in SSc. Randomized controlled trials (RCTs) and retrospective studies comparing AHSCT with standard immunosuppressive therapy were included. Of 363 titles screened from multiple databases, 15 were extracted for further investigation, and 4 met inclusion criteria (3 RCTs and 1 retrospective analysis). The control arm was monthly cyclophosphamide in all the RCTs and the majority of patients in the retrospective analysis (69%). Compared with the control, AHSCT reduced all-cause mortality (risk ratio [RR], .5 [95% confidence interval, .33 to .75]) and improved skin thickness (modified Rodnan skin score mean difference [MD], 10.62 [95% CI, -14.21 to 7.03]), forced vital capacity (MD, 9.58 [95% CI, 3.89 to 15.18]), total lung capacity (MD, 6.36 [95% CI, 1.23 to 11.49]), and quality of life (physical 36-Item Short Form Health Survey [MD, 6.99 (95% CI, 2.79 to 11.18)]). Treatment-related mortality considerably varied between trials but was overall higher with AHSCT (RR, 9.00 [95% CI, 1.57 to 51.69]). The risk of bias for studies included in the analysis was low. Overall, AHSCT reduces the risk of all-cause mortality and has properties of a disease-modifying antirheumatic treatment in SSc. Further investigation is warranted for refining patient selection and timing of transplantation.
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Affiliation(s)
- Roni Shouval
- Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Ramat-Gan, Israel; Dr. Pinchas Bornstein Talpiot Medical Leadership Program, Chaim Sheba Medical Center, Ramat-Gan, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
| | - Nadav Furie
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Internal Medicine F, Chaim Sheba Medical Center, Ramat-Gan, Israel
| | - Pia Raanani
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Institute of Hematology, Davidoff Cancer Center, Beilinson Hospital, Rabin Medical Center, Petah-Tikva, Israel
| | - Arnon Nagler
- Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Ramat-Gan, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Anat Gafter-Gvili
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Institute of Hematology, Davidoff Cancer Center, Beilinson Hospital, Rabin Medical Center, Petah-Tikva, Israel; Internal Medicine A, Beilinson Hospital, Rabin Medical Center, Petah-Tikva, Israel
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27
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van Rhijn-Brouwer FCC, Spierings J, van Laar JM. Autologous hematopoietic stem cell transplantation in systemic sclerosis: A reset to tolerance? Immunol Lett 2017; 195:88-96. [PMID: 29155233 DOI: 10.1016/j.imlet.2017.11.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Revised: 11/01/2017] [Accepted: 11/15/2017] [Indexed: 12/29/2022]
Abstract
Autologous hematopoietic stem cell transplantation (ASCT) is an effective therapy for refractory autoimmune disease, in particular diffuse cutaneous systemic sclerosis (dcSSc). ASCT is the only treatment that can induce long term remission in dcSSc. However, the mechanism of action of ASCT has not yet been fully elucidated. The current hypothesis is that ASCT induces a long term 'reset' of the immune system, but there is no clear definition yet of such an immunological 'reset to tolerance', nor has it been established how to distinguish a 'reset' from long term immunosuppression. Here, we review the literature on immunological changes after ASCT in dcSSc patients to gain more insight whether changes in immunological parameters can help elucidate the mechanism of action of ASCT. We identified 12 studies. While some immunological parameters could be correlated to clinical response, heterogeneity in the studies, short follow-up time and the small sample sizes preclude firm conclusions. Importantly, most patients displayed a sustained clinical response despite the presence of auto-antibodies or higher-than-normal concentrations of cytokines and proteins associated with disease activity. This suggests that the mechanism of ASCT may not be solely immunological. Future research should focus on larger cohorts of patients and also take functional evaluation of immune cells into account in order to determine whether ASCT induces long term immunosuppression or resets the immune system to tolerance. Answering this question is key to further optimizing ASCT for dcSSc patients.
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Affiliation(s)
- Femke C C van Rhijn-Brouwer
- Department of Nephrology and Hypertension, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands; Department of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands
| | - Julia Spierings
- Department of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands
| | - Jacob M van Laar
- Department of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
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28
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Farge D, Arruda LCM, Brigant F, Clave E, Douay C, Marjanovic Z, Deligny C, Maki G, Gluckman E, Toubert A, Moins-Teisserenc H. Long-term immune reconstitution and T cell repertoire analysis after autologous hematopoietic stem cell transplantation in systemic sclerosis patients. J Hematol Oncol 2017; 10:21. [PMID: 28103947 PMCID: PMC5244700 DOI: 10.1186/s13045-016-0388-5] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Accepted: 12/30/2016] [Indexed: 02/08/2023] Open
Abstract
The determinants of clinical responses after autologous hematopoietic stem cell transplantation (aHSCT) in systemic sclerosis (SSc) are still unraveled. We analyzed long-term immune reconstitution (IR) and T cell receptor (TCR) repertoire diversity in 10 SSc patients, with at least 6 years simultaneous clinical and immunological follow-up after aHSCT. Patients were retrospectively classified as long-term responders (A, n = 5) or non-responders (B, n = 5), using modified Rodnan’s skin score (mRSS) and forced vital capacity (FVC%). All patients had similar severe SSc before aHSCT. Number of reinjected CD34+ cells was higher in group B versus A (P = 0.02). Long-term mRSS fall >25% was more pronounced in group A (P = 0.004), the only to improve long-term FVC% >10% (P = 0.026). There was an overall trend toward increased of T cell reconstitution in group B versus A. B cells had a positive linear regression slope in group A (LRS = 11.1) and negative in group B (LRS = −11.6). TCR repertoire was disturbed before aHSCT and the percentage of polyclonal families significantly increased at long-term (P = 0.046), with no difference between groups. Despite improved skin score after aHSCT in all SSc patients, pretransplant B cell clonal expansion and faster post-transplant T cell IR in long-term non-responder/relapsing patients call for new therapeutic protocols guided by IR analysis to improve their outcome.
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Affiliation(s)
- Dominique Farge
- Unité de Médecine Interne, Maladies Autoimmunes et Pathologie Vasculaire, UF 04, Assistance Publique Hopitaux de Paris AP-HP, Hôpital Saint-Louis, Paris, France. .,INSERM UMR-1160, Institut Universitaire d'Hématologie, Paris, France. .,Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
| | - Lucas C M Arruda
- INSERM UMR-1160, Institut Universitaire d'Hématologie, Paris, France.,Center for Cell-based Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto, Brazil.,Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Fanny Brigant
- INSERM UMR-1160, Institut Universitaire d'Hématologie, Paris, France
| | - Emmanuel Clave
- INSERM UMR-1160, Institut Universitaire d'Hématologie, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Corinne Douay
- INSERM UMR-1160, Institut Universitaire d'Hématologie, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Zora Marjanovic
- Département d'Hématologie, AP-HP, Hôpital Saint-Antoine, Paris, France
| | - Christophe Deligny
- Service de Médecine Interne, Hôpital Pierre Zobda Quitman, Fort-de France, Martinique, France
| | - Guitta Maki
- Laboratoire d'Immunologie-Histocompatibilité, AP-HP, Hôpital Saint Louis, Paris, France
| | - Eliane Gluckman
- Eurocord-Monacord, AP-HP, Hôpital Saint-Louis, Paris, France.,Centre Scientifique de Monaco, Monaco, France
| | - Antoine Toubert
- INSERM UMR-1160, Institut Universitaire d'Hématologie, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Paris, France.,Laboratoire d'Immunologie-Histocompatibilité, AP-HP, Hôpital Saint Louis, Paris, France
| | - Helene Moins-Teisserenc
- INSERM UMR-1160, Institut Universitaire d'Hématologie, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Paris, France.,Laboratoire d'Immunologie-Histocompatibilité, AP-HP, Hôpital Saint Louis, Paris, France
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29
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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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30
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Jauregui-Amezaga A, Rovira M, Marín P, Salas A, Pinó-Donnay S, Feu F, Elizalde JI, Fernández-Avilés F, Martínez C, Gutiérrez G, Rosiñol L, Carreras E, Urbano A, Lozano M, Cid J, Suárez-Lledó M, Mensa J, Rimola J, Rodríguez S, Masamunt MC, Comas D, Ruíz I, Ramírez-Morros A, Gallego M, Ordás I, Panés J, Ricart E. Improving safety of autologous haematopoietic stem cell transplantation in patients with Crohn's disease. Gut 2016; 65:1456-62. [PMID: 26585938 DOI: 10.1136/gutjnl-2015-309836] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Accepted: 10/24/2015] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To evaluate the feasibility and toxicity of autologous haematopoietic stem cell transplantation (HSCT) for the treatment of refractory Crohn's disease (CD). DESIGN In this prospective study, patients with refractory CD suffering an aggressive disease course despite medical treatment, impaired quality of life and in whom surgery was not an acceptable option underwent HSCT. Toxicity and complications during the procedure and within the first year following transplantation were evaluated, along with the impact of the introduction of supportive measures on safety outcomes. RESULTS 26 patients were enrolled. During mobilisation, 16 patients (62%) presented febrile neutropaenia, including one bacteraemia and two septic shocks. Neutropaenia median time after mobilisation was 5 days. 5 patients withdrew from the study after mobilisation and 21 patients entered the conditioning phase. Haematopoietic recovery median time for neutrophils (>0.5×10(9)/L) was 11 days and for platelets (>20×10(9)/L) 4 days. Twenty patients (95%) suffered febrile neutropaenia and three patients (27%) presented worsening of the perianal CD activity during conditioning. Among non-infectious complications, 6 patients (28.5%) presented antithymocyte globulin reaction, 12 patients (57%) developed mucositis and 2 patients (9.5%) had haemorrhagic complications. Changes in supportive measures over the study, particularly antibiotic prophylaxis regimes during mobilisation and conditioning, markedly diminished the incidence of severe complications. During the first 12-month follow-up, viral infections were the most commonly observed complications, and one patient died due to systemic cytomegalovirus infection. CONCLUSIONS Autologous HSCT for patients with refractory CD is feasible, but extraordinary supportive measures need to be implemented. We suggest that this procedure should only be performed in highly experienced centres.
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Affiliation(s)
| | - Montserrat Rovira
- Hematology Department, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Pedro Marín
- Hemotherapy and Hemostasis Department, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Azucena Salas
- Gastroenterology Department, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Susana Pinó-Donnay
- Gastroenterology Department, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Faust Feu
- Gastroenterology Department, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - J Ignasi Elizalde
- Gastroenterology Department, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | | | - Carmen Martínez
- Hematology Department, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Gonzalo Gutiérrez
- Hematology Department, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Laura Rosiñol
- Hematology Department, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Enric Carreras
- Hematology Department, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Alvaro Urbano
- Hematology Department, 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
| | | | - Josep Mensa
- Infectious Diseases Department, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Jordi Rimola
- Radiology Department, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Sonia Rodríguez
- Radiology Department, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Mari Carme Masamunt
- Gastroenterology Department, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Dolors Comas
- Gastroenterology Department, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Irene Ruíz
- Hematology Department, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Anna Ramírez-Morros
- Gastroenterology Department, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Marta Gallego
- Gastroenterology Department, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Ingrid Ordás
- Gastroenterology Department, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Julian Panés
- Gastroenterology Department, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Elena Ricart
- Gastroenterology Department, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
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31
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[Autologous stem cell transplantation in systemic sclerosis]. Z Rheumatol 2016; 75:762-769. [PMID: 27510996 DOI: 10.1007/s00393-016-0168-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Autologous hematopoietic stem cell transplantation (HSCT) is a very effective treatment option for patients with severe systemic sclerosis (SSc). In addition to various case series two randomized controlled trials could prove its superiority over intense cyclophosphamide pulse therapy. Nevertheless, HSCT is associated with a treatment-related mortality of approximately 10 %; therefore, further studies should be carried out to reduce the toxicity of HSCT by adaptation of the therapy regimen and the option of HSCT should be made available earlier to patients with a high risk of mortality. The mechanism of action of HSCT is still poorly understood. While profibrotic cytokines or even autoantibodies hardly appear to be influenced by the treatment, alterations to regulatory T‑cells may play a role. Further improvement of transplantation regimens as well as a better understanding of the underlying pathogenetic principles and mechanisms of action should be the aim of further studies on HSCT.
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32
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Arruda LCM, Clave E, Moins-Teisserenc H, Douay C, Farge D, Toubert A. Resetting the immune response after autologous hematopoietic stem cell transplantation for autoimmune diseases. Curr Res Transl Med 2016; 64:107-13. [PMID: 27316394 DOI: 10.1016/j.retram.2016.03.004] [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: 03/16/2016] [Accepted: 03/31/2016] [Indexed: 12/21/2022]
Abstract
Autologous hematopoietic stem cell transplantation (AHSCT) is currently investigated as treatment for severe and refractory autoimmune diseases, such as multiple sclerosis (MS), systemic sclerosis (SSc), Crohn's disease (CD) and systemic lupus erythematosus. Randomized clinical trials in MS, SSc and CD have shown the efficacy of AHSCT to promote control of disease activity and progression, when compared to conventional treatment. The use of high dose immunosuppressive conditioning is essential to eliminate the autoimmune repertoire, and the re-infusion of autologous hematopoietic stem cells avoids long-term leucopenia by reconstitution of both immune and hematological systems. Recent studies showed that AHSCT is able to deplete the autoimmune compartment and further promote the formation of a new auto-tolerant immune repertoire, reducing the inflammatory milieu and leading to long-term clinical remission without any complementary post-graft treatment. Deep knowledge about the mechanisms of action related to AHSCT-induced remission is required for the management of possible post-AHSCT relapse and improvement of clinical protocols. This paper will review the mechanisms enrolled in the immune response resetting promoted by AHSCT in patients with autoimmune diseases.
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Affiliation(s)
- L C M Arruda
- Center for Cell-based Therapy, São Paulo Research Foundation (FAPESP), Ribeirão Preto, Brazil; Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
| | - E Clave
- Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France; INSERM UMR1160, Paris, France; Laboratoire d'Immunologie et d'Histocompatibilité, Hôpital Saint-Louis, AP-HP, Paris, France
| | - H Moins-Teisserenc
- Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France; INSERM UMR1160, Paris, France; Laboratoire d'Immunologie et d'Histocompatibilité, Hôpital Saint-Louis, AP-HP, Paris, France
| | - C Douay
- Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France; INSERM UMR1160, Paris, France; Laboratoire d'Immunologie et d'Histocompatibilité, Hôpital Saint-Louis, AP-HP, Paris, France
| | - D Farge
- Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France; INSERM UMR1160, Paris, France; Unité Clinique de Médecine Interne, Maladies Autoimmunes et Pathologie Vasculaire, UF 04, Hôpital Saint-Louis, AP-HP, Assistance Publique des Hôpitaux de Paris, 75010 Paris, France
| | - A Toubert
- Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France; INSERM UMR1160, Paris, France; Laboratoire d'Immunologie et d'Histocompatibilité, Hôpital Saint-Louis, AP-HP, Paris, France
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33
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Maria ATJ, Maumus M, Le Quellec A, Jorgensen C, Noël D, Guilpain P. Adipose-Derived Mesenchymal Stem Cells in Autoimmune Disorders: State of the Art and Perspectives for Systemic Sclerosis. Clin Rev Allergy Immunol 2016; 52:234-259. [DOI: 10.1007/s12016-016-8552-9] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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34
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Guillaume-Jugnot P, Daumas A, Magalon J, Sautereau N, Veran J, Magalon G, Sabatier F, Granel B. State of the art. Autologous fat graft and adipose tissue-derived stromal vascular fraction injection for hand therapy in systemic sclerosis patients. Curr Res Transl Med 2016; 64:35-42. [PMID: 27140597 DOI: 10.1016/j.retram.2016.01.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2015] [Accepted: 01/04/2016] [Indexed: 01/27/2023]
Abstract
Systemic sclerosis is an autoimmune disease characterized by sclerosis (hardening) of the skin and deep viscera associated with microvascular functional and structural alteration, which leads to chronic ischemia. In the hands of patients, ischemic and fibrotic damages lead to both pain and functional impairment. Hand disability creates a large burden in professional and daily activities, with social and psychological consequences. Currently, the proposed therapeutic options for hands rely mainly on hygienic measures, vasodilatator drugs and physiotherapy, but have many constraints and limited effects. Developing an innovative therapeutic approach is crucial to reduce symptoms and improve the quality of life. The discovery of adult stem cells from adipose tissue has increased the interest to use adipose tissue in plastic and regenerative surgery. Prepared as freshly isolated cells for immediate autologous transplantation, adipose tissue-derived stem cell therapy has emerged as a therapeutic alternative for the regeneration and repair of damaged tissues. We aim to update literature in the interest of autologous fat graft or adipose derived from stromal vascular fraction cell-based therapy for the hands of patients who suffer from systemic sclerosis.
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Affiliation(s)
- P Guillaume-Jugnot
- Service de médecine interne, hôpital Nord, Assistance publique-Hôpitaux de Marseille (AP-HM), 13915 Marseille cedex 05, France
| | - A Daumas
- Service de médecine interne, gériatrie et thérapeutique, hôpital de la Timone, AP-HM, 13385 Marseille cedex 05, France
| | - J Magalon
- Laboratoire de culture et thérapie cellulaire, Inserm CBT-1409, hôpital de la Conception, AP-HM, 13385 Marseille cedex 05, France
| | - N Sautereau
- Service de médecine interne, hôpital Nord, Assistance publique-Hôpitaux de Marseille (AP-HM), 13915 Marseille cedex 05, France
| | - J Veran
- Laboratoire de culture et thérapie cellulaire, Inserm CBT-1409, hôpital de la Conception, AP-HM, 13385 Marseille cedex 05, France
| | - G Magalon
- Service de chirurgie plastique et réparatrice, hôpital de la Conception, AP-HM, 13385 Marseille cedex 05, France
| | - F Sabatier
- Laboratoire de culture et thérapie cellulaire, Inserm CBT-1409, hôpital de la Conception, AP-HM, 13385 Marseille cedex 05, France; Inserm UMR 1076 Vascular Research Centre of Marseille, Aix-Marseille université, 13385 Marseille cedex 05, France
| | - B Granel
- Service de médecine interne, hôpital Nord, Assistance publique-Hôpitaux de Marseille (AP-HM), 13915 Marseille cedex 05, France; Inserm UMR 1076 Vascular Research Centre of Marseille, Aix-Marseille université, 13385 Marseille cedex 05, France.
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35
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Oliveira MC, Labopin M, Henes J, Moore J, Del Papa N, Cras A, Sakellari I, Schroers R, Scherer HU, Cuneo A, Kyrcz-Krzemien S, Daikeler T, Alexander T, Finke J, Badoglio M, Simões B, Snowden JA, Farge D, Farge D. Does ex vivo CD34+ positive selection influence outcome after autologous hematopoietic stem cell transplantation in systemic sclerosis patients? Bone Marrow Transplant 2015; 51:501-5. [PMID: 26642332 DOI: 10.1038/bmt.2015.299] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Revised: 10/22/2015] [Accepted: 10/23/2015] [Indexed: 12/20/2022]
Abstract
This EBMT Autoimmune Disease Working Party study aimed to evaluate the influence of CD34+ positive graft selection (CD34+) on the outcome of systemic sclerosis (SSc) patients after autologous hematopoietic stem cell transplantation (AHSCT). Clinical and laboratory data from 138 SSc patients at diagnosis, before and after AHSCT were retrospectively analyzed. CD34+ selection was performed in 47.1% (n=65) patients. By multivariate analysis adjusting for all factors differing between the two groups (without or with CD34+), there was no statistically significant difference in terms of overall survival (hazard ratio (HR): 0.98, 95% confidence interval (CI) 0.40-2.39, P=0.96), PFS (HR: 1.55, 95% CI 0.83-2.88, P=0.17) and incidence of relapse or progression (HR: 1.70, 95% CI 0.85-3.38, P=0.13). We demonstrate that CD34+ does not add benefit to the outcome of SSc patient treated with AHSCT. These findings should be further confirmed by prospective randomized trials.
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Affiliation(s)
- M C Oliveira
- Division of Clinical Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - M Labopin
- EBMT, Hôpital Saint Antoine, Paris, France
| | - J Henes
- Medizinische Universitätsklinik Abt. II, Tübingen, Germany
| | - J Moore
- Department of Haematology, St Vincent's Hospital, Sydney, New South Wales, Australia
| | - N Del Papa
- Scleroderma Clinic, U.O.C. Day Hospital Rheumatology, Osp. G. Pini, Milan, Italy
| | - A Cras
- Assistance Publique-Hôpitaux de Paris, Saint-Louis Hospital, Cell Therapy Unit, Cord Blood Bank and CIC-BT501, Paris, France.,INSERM UMRS 1140, Paris Descartes, Faculté de Pharmacie, Paris, France
| | - I Sakellari
- Bone Marrow Transplantation Unit, George Papanicolaou General Hospital, Thessaloniki, Greece
| | - R Schroers
- Ruhr-Universität Bochum, Medizinische Klinik Knappschaftskrankenhaus, Bochum, Germany
| | - H U Scherer
- Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands
| | - A Cuneo
- University of Ferrara-St Anna Hospital, Ferrara, Italy
| | - S Kyrcz-Krzemien
- Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia, Katowice, Poland
| | - T Daikeler
- Department of Rheumatology, University Hospital Basel, Basel, Switzerland
| | - T Alexander
- Department of Rheumatology and Clinical Immunology, Charité-University Medicine Berlin, Berlin, Germany
| | - J Finke
- Department of Medicine-Hematology and Oncology, University of Freiburg, Freiburg, Germany
| | - M Badoglio
- EBMT Paris Office, Hôpital Saint Antoine, Paris, France
| | - B Simões
- Division of Hematology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - J A Snowden
- Department of Hematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - D Farge
- Paris 7 University, INSERM U1160, Paris, France.,Unité de Médecine Interne et Pathologie Vasculaire, Saint Louis Hospital, Assistance Publique des Hôpitaux de Paris, Paris 7 Denis Diderot University, Paris, France
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Bruera S, Siddhanamatha HR, Molony DA, Mayes MD, Lopez-Olivo MA. Stem cell transplantation for systemic sclerosis. Hippokratia 2015. [DOI: 10.1002/14651858.cd011819] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- Sebastian Bruera
- Baylor College of Medicine; Department of Internal Medicine; 1 Baylor Plaza Houston Texas USA 77030
| | - Harish R Siddhanamatha
- The University of Texas, M.D. Anderson Cancer Center; Department of General Internal Medicine; 1515 Holcombe Blvd. Unit 1465 Houston Texas USA 77030
| | - Donald A Molony
- UT-Houston Health Science Center; Internal Medicine; Division of Renal Diseases and Hypertension 64312 Fannin St Houston TX USA 77030
| | - Maureen D Mayes
- The University of Texas at Houston Medical School; Division of Rheumatology and Clinical Immunogenetics; 6431 Fannin St., MSB 5.270 Houston Texas USA 77030
| | - Maria Angeles Lopez-Olivo
- The University of Texas, M.D. Anderson Cancer Center; Department of General Internal Medicine; 1515 Holcombe Blvd. Unit 1465 Houston Texas USA 77030
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van Laar JM, Naraghi K, Tyndall A. Haematopoietic stem cell transplantation for poor-prognosis systemic sclerosis. Rheumatology (Oxford) 2015; 54:2126-33. [PMID: 25953700 DOI: 10.1093/rheumatology/kev117] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Indexed: 12/29/2022] Open
Abstract
Haematopoietic stem cell transplantation (HSCT) following intensive immune suppression has been used in >2000 patients with severe autoimmune diseases for 18 years, including 300 with SSc. The concept is to profoundly reduce the bulk of auto-aggressive immune competent cells and then rescue the patient's ablated haematopoiesis via an autologous HSCT. An early analysis of uncontrolled phase I/II data suggested that approximately one-third of these achieved a substantial improvement, with a relapse rate of 25% and a treatment-related mortality ranging from 6% to 23% across different studies. These early results led to three prospective randomized controlled trials, two of which are completed, confirming that HSCT shows clear advantages over conventional immunosuppression, but with significant toxicity. In some patients, sustained complete normalization of skin changes, reversal of positive autoantibody status and withdrawal of immunosuppressive medication were observed. These results attest to the profound effects of HSCT.
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Affiliation(s)
- Jacob M van Laar
- Department of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands,
| | - Kamran Naraghi
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Chapel Allerton Hospital, Leeds, UK and
| | - Alan Tyndall
- Department of Rheumatology, University Hospital, Basel, Switzerland
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Stem cell autograft and allograft in autoimmune diseases. Clin Exp Med 2014; 16:13-20. [PMID: 25501897 DOI: 10.1007/s10238-014-0330-5] [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: 10/01/2014] [Accepted: 12/06/2014] [Indexed: 10/24/2022]
Abstract
Autoimmune diseases are characterized by an insufficiency of immune tolerance and, although treated with a number of useful drugs, may need more unconventional therapeutic strategies for their more severe presentations. Among such unconventional therapeutic approaches, stem cell autograft and allograft have been used, with the aim of stimulating disease remission by modifying the pathogenic mechanisms that induce anomalous responses against self-antigens. Autologous transplantation is performed with the purpose of retuning autoimmune cells, whereas allogeneic transplantation is performed with the purpose of replacing anomalous immune effectors and mediators. In this article, we comprehensively review up-to-date information on the autoimmune diseases for which the transplantation of stem cells is indicated.
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Farge D, Terriou L, Badoglio M, Cras A, Desreumaux P, Hadj-Khelifa S, Marjanovic Z, Moisan A, Dulery R, Faucher C, Hij A, Martin T, Vermersch P, Yakoub-Agha I. Autogreffe des cellules souches hématopoïétiques dans les maladies auto-immunes : recommandations de la SFGM-TC. ACTA ACUST UNITED AC 2014; 62:204-8. [DOI: 10.1016/j.patbio.2014.05.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Accepted: 05/26/2014] [Indexed: 12/29/2022]
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Abstract
PURPOSE OF REVIEW The purpose of this review is to discuss recent published clinical and mechanistic studies on stem cell transplantation for systemic sclerosis and their implications for clinical practice. RECENT FINDINGS Retrospective analyses of independent cohorts of systemic sclerosis patients treated with autologous stem cell transplantation showed significant improvement of skin thickening, lung function and quality of life, but at the expense of 6-17% treatment-related mortality. Right heart catheterization was employed in one study to identify and exclude patients at risk of serious cardiopulmonary toxicity. The superior efficacy of stem cell transplantation versus intravenous pulses cyclophosphamide was demonstrated in a small randomized, controlled phase 2 trial in 19 systemic sclerosis patients and a large randomized phase 3 trial in 156 patients with severe diffuse cutaneous systemic sclerosis. The latter also showed a survival benefit of transplanted patients despite a 10% transplant-related mortality. Mechanistic studies in transplanted patients have shown major shifts in circulating natural killer cells, T and B lymphocytes immediately after stem cell transplantation, similar to those observed in other autoimmune conditions. Stem cell transplantation of systemic sclerosis patients with lung involvement resulted in demonstrable attenuation of thoracic high-resolution CT (HRCT) abnormalities and serum markers of lung fibrosis. SUMMARY Stem cell transplantation is an effective treatment option for patients with severe systemic sclerosis, but is associated with toxicity and treatment-related mortality. The available data suggest that patient selection and comprehensive cardiopulmonary screening are critical factors in determining outcome. VIDEO ABSTRACT AVAILABLE See the Supplementary Digital content 1 (http://links.lww.com/COR/A7).
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Naraghi K, van Laar JM. Update on stem cell transplantation for systemic sclerosis: recent trial results. Curr Rheumatol Rep 2013; 15:326. [PMID: 23516015 DOI: 10.1007/s11926-013-0326-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Systemic sclerosis (SSc) is a heterogeneous condition characterized by the deposition of excess collagen in skin and internal organs due to vasculopathy, immune activation, low grade inflammation, and fibrosis. Progressive diffuse cutaneous SSc with organ involvement has a poor prognosis. The employment of autologous hematopoietic stem cell transplantation (HSCT) as a means to escalate immunosuppressive therapy has resulted in rapid and sustained improvement of skin thickening and functional ability, stabilization of major organ function with some improvement of vital capacity in pilot studies, registry analyses, and the phase II ASSIST trial. Results from the phase III ASTIS trial corroborate these findings and show long-term survival benefit of HSCT. The ASTIS and SCOT trials will determine whether the benefits of HSCT outweigh the risks of serious adverse events including treatment-related mortality of around 6-10% and potential long-term complications. Better patient selection and safer transplant regimens may improve the outcome of HSCT for SSc.
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Affiliation(s)
- Kamran Naraghi
- Department of Rheumatology, The James Cook University Hospital, Middlesbrough, UK
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42
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Burt RK, Oliveira MC, Shah SJ, Moraes DA, Simoes B, Gheorghiade M, Schroeder J, Ruderman E, Farge D, Chai ZJ, Marjanovic Z, Jain S, Morgan A, Milanetti F, Han X, Jovanovic B, Helenowski IB, Voltarelli J. Cardiac involvement and treatment-related mortality after non-myeloablative haemopoietic stem-cell transplantation with unselected autologous peripheral blood for patients with systemic sclerosis: a retrospective analysis. Lancet 2013; 381:1116-24. [PMID: 23363664 DOI: 10.1016/s0140-6736(12)62114-x] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND Autologous haemopoietic stem-cell transplantation (HSCT) benefits patients with systemic sclerosis but has been associated with significant treatment-related mortality and failure to improve diffusion capacity of carbon monoxide (DLCO). We aimed to assess efficacy of HSCT and use of rigorous cardiac screening in this group. METHODS We assessed patients with diffuse systemic sclerosis or limited systemic sclerosis and interstitial lung disease who were treated with HSCT as part of a study or on a compassionate basis at Northwestern University (Chicago, IL, USA) or the University of São Paulo (Ribeirão Preto, Brazil). Unselected peripheral blood stem cells were harvested with cyclophosphamide (2 g/m(2)) and filgrastim. The transplant regimen was a non-myeloablative regimen of cyclophosphamide (200 mg/kg) and rabbit anti-thymocyte globulin (rATG; 4·5-6·5 mg/kg). We followed patients up to 5 years for overall survival, relapse-free survival, modified Rodnan skin score, and pulmonary function tests. FINDINGS Five (6%) of 90 patients died from treatment-related causes. Despite standard guidelines that recommend echocardiogram for screening before transplantation, four treatment-related deaths occurred because of cardiovascular complications (one constrictive pericarditis, two right heart failures without underlying infection, and one heart failure during mobilisation), and one death was secondary to sepsis without documented underlying heart disease. Kaplan-Meier analysis showed survival was 78% at 5 years (after eight relapse-related deaths) and relapse-free survival was 70% at 5 years. Compared with baseline, we noted improvements after HSCT in modified Rodnan skin scores at 1 year (58 patients; p<0·0001), 2 years (42 patients; p<0·0001), and 3 years (27 patients; p<0·0001) and forced vital capacity at 1 year (58 patients; p=0·009), 2 years (40 patients; p=0·02), and 3 years (28 patients; p=0·004), but total lung capacity and DLCO were not improved significantly after HSCT. Overall mean DLCO was significantly improved in patients with normal baseline echocardiograms (p=0·005) or electrocardiographs (p=0·05). INTERPRETATION Autologous HSCT with a non-myeloablative regimen of cyclophosphamide and rATG with a non-selected autograft results in sustained improvement in skin thickness and forced vital capacity. DLCO is affected by baseline cardiac function. Guidelines for cardiac screening of patients with systemic sclerosis to assess treatment-related risk from pulmonary artery hypertension, primary cardiac involvement, or pericardial disease should be reconsidered and updated. FUNDING None.
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Affiliation(s)
- Richard K Burt
- Division of Immunotherapy, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
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Cipriani P, Carubbi F, Liakouli V, Marrelli A, Perricone C, Perricone R, Alesse E, Giacomelli R. Stem cells in autoimmune diseases: Implications for pathogenesis and future trends in therapy. Autoimmun Rev 2012. [PMID: 23183379 DOI: 10.1016/j.autrev.2012.10.004] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
In this review we report the recent progresses, available in the literature, concerning the biology and the potential therapeutic role of both mesenchymal stem cells (MSCs) and hematopoietic stem cells in autoimmune diseases. Mesenchymal stem cells (MSCs) are responsible for the normal turnover and maintenance of adult mesenchymal tissues and their pleiotropic nature allows them to sense and respond to an event in the local environment, be it injury or inflammation. Recently, MSCs have been shown to have immune-modulatory properties and immunosuppressive capacities, acting on different immune cells both in vitro and in vivo, in addition to an immunologically privileged phenotype. Moreover, several works suggest that MSCs are defective in autoimmune diseases. These aspects are now considered the most intriguing aspect of their biology, introducing the possibility that these cells might be used as effective therapy in autoimmune diseases. Autoimmune diseases represent a failure of normal immune regulatory processes as they are characterized by activation and expansion of immune cell subsets in response to non-pathogenic stimuli. As autoimmune diseases can be transferred, or alternatively, cured, by stem cell transplantation, a defect in the hemopoietic stem cell as a cause of autoimmune diseases may be postulated. The rationale for autologous hematopoietic stem cell transplantation (HSCT) in autoimmune diseases is the ablation of an aberrant or self-reactive immune system by chemotherapy and regeneration of a new and hopefully self-tolerant immune system from hematopoietic stem cells. In the past 15years, more than 1500 patients worldwide have received HSCT, mostly autologous, as treatment for a severe autoimmune disease and the majority were affected by multiple sclerosis, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis, juvenile idiopathic arthritis and idiopathic cytopenic purpura.
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Affiliation(s)
- Paola Cipriani
- Rheumatology Unit, Clinical Science and Biotechnology Department, University of L'Aquila, Italy.
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Snowden JA, Saccardi R, Allez M, Ardizzone S, Arnold R, Cervera R, Denton C, Hawkey C, Labopin M, Mancardi G, Martin R, Moore JJ, Passweg J, Peters C, Rabusin M, Rovira M, van Laar JM, Farge D. Haematopoietic SCT in severe autoimmune diseases: updated guidelines of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 2012; 47:770-90. [PMID: 22002489 PMCID: PMC3371413 DOI: 10.1038/bmt.2011.185] [Citation(s) in RCA: 212] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2011] [Revised: 07/04/2011] [Accepted: 07/04/2011] [Indexed: 12/13/2022]
Abstract
In 1997, the first consensus guidelines for haematopoietic SCT (HSCT) in autoimmune diseases (ADs) were published, while an international coordinated clinical programme was launched. These guidelines provided broad principles for the field over the following decade and were accompanied by comprehensive data collection in the European Group for Blood and Marrow Transplantation (EBMT) AD Registry. Subsequently, retrospective analyses and prospective phase I/II studies generated evidence to support the feasibility, safety and efficacy of HSCT in several types of severe, treatment-resistant ADs, which became the basis for larger-scale phase II and III studies. In parallel, there has also been an era of immense progress in biological therapy in ADs. The aim of this document is to provide revised and updated guidelines for both the current application and future development of HSCT in ADs in relation to the benefits, risks and health economic considerations of other modern treatments. Patient safety considerations are central to guidance on patient selection and HSCT procedural aspects within appropriately experienced and Joint Accreditation Committee of International Society for Cellular Therapy and EBMT accredited centres. A need for prospective interventional and non-interventional studies, where feasible, along with systematic data reporting, in accordance with EBMT policies and procedures, is emphasized.
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Affiliation(s)
- J A Snowden
- Department of Haematology, Sheffield Teaching Hospitals NHS Trust, Sheffield, UK
- Department of Oncology, University of Sheffield, Sheffield, UK
| | - R Saccardi
- Department of Haematology, Careggi University Hospital, Firenze, Italy
| | - M Allez
- Service de Gastroentérologie, INSERM U 662, Hôpital St Louis, Paris, France
| | - S Ardizzone
- Department of Gastroenterology, Sacco University Hospital, Milan, Italy
| | - R Arnold
- Charite Hospital Berlin, Berlin, Germany
| | - R Cervera
- Department of Autoimmune Diseases, Hospital Clinic, Barcelona, Spain
| | - C Denton
- Centre for Rheumatology, Royal Free and University College Medical School, Hampstead, London, UK
| | - C Hawkey
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK
| | - M Labopin
- Hôpital Saint Antoine, Service d'Hématologie et Thérapie Cellulaire, AP-HP, UPMC Univ Paris 06, Paris, France
| | - G Mancardi
- Department of Neuroscience, Ophthalmology and Genetics, University of Genova, Genova, Italy
| | - R Martin
- Institute for Neuroimmunology and Clinical MS Research, Hamburg, Germany
| | - J J Moore
- St Vincent's Hospital, Sydney, NSW, Australia
| | - J Passweg
- Universitaetsspital Basel, Basel, Switzerland
| | - C Peters
- BMT Unit, St Anna Children's Hospital, Vienna, Austria
| | - M Rabusin
- BMT Unit, Department of Pediatrics, Institute of Maternal and Child Health Burlo Garofolo, Trieste, Italy
| | - M Rovira
- SCT Unit, Hematology Department, Hospital Clinic, Barcelona, Spain
| | | | - D Farge
- Department of Internal Medicine, INSERM U 796, Hôpital St Louis, Paris, France
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Burt RK, Milanetti F. Hematopoietic stem cell transplantation for systemic sclerosis: history and current status. Curr Opin Rheumatol 2012; 23:519-29. [PMID: 21857226 DOI: 10.1097/bor.0b013e32834aa45f] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW Systemic sclerosis (SSc) remains one of the last severe autoimmune disease with a poor prognosis and modest response to immunosuppressive therapy. Mortality in severe diffuse disease with internal organ involvement is elevated. Autologous hematopoietic transplantation (HSCT) has emerged in the last decade as a promising disease-modifying treatment. RECENT FINDINGS In phase I/II trials, HSCT has demonstrated to induce impressive reversal of skin fibrosis, neoangiogenesis, improved functionality and quality of life, and stabilization of internal organ function. Treatment-related mortality was reduced over time by better pretransplant evaluation and by treating patients earlier in disease. SUMMARY Two out of three randomized trials of autologous HSCT for SSc have been concluded: the nonmyeloablative American Systemic Sclerosis Immune Suppression versus Transplant, and Autologous Stem cell Transplantation International Scleroderma. The myeloablative Scleroderma Cyclophosphamide versus Transplant instead is still recruiting patients. The soon expected results from these trials should clarify the role of autologous HSCT in the challenging management of severe SSc.
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Affiliation(s)
- Richard K Burt
- Division of Immunotherapy, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
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Burt RK, Shah SJ, Dill K, Grant T, Gheorghiade M, Schroeder J, Craig R, Hirano I, Marshall K, Ruderman E, Jovanovic B, Milanetti F, Jain S, Boyce K, Morgan A, Carr J, Barr W. Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial. Lancet 2011; 378:498-506. [PMID: 21777972 DOI: 10.1016/s0140-6736(11)60982-3] [Citation(s) in RCA: 374] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Non-randomised studies of haemopoietic stem-cell transplantation (HSCT) in systemic sclerosis have shown improvements in lung function and skin flexibility but high treatment-related mortality. We aimed to assess safety and efficacy of autologous non-myeloablative HSCT in a phase 2 trial compared with the standard of care, cyclophosphamide. METHODS In our open-label, randomised, controlled phase 2 trial, we consecutively enrolled patients at Northwestern Memorial Hospital (Chicago, IL, USA) who were aged younger than 60 years with diffuse systemic sclerosis, modified Rodnan skin scores (mRSS) of more than 14, and internal organ involvement or restricted skin involvement (mRSS <14) but coexistent pulmonary involvement. We randomly allocated patients 1:1 by use of a computer-generated sequence with a mixed block design (blocks of ten and four) to receive HSCT, 200 mg/kg intravenous cyclophosphamide, and 6·5 mg/kg intravenous rabbit antithymocyte globulin or to receive 1·0 g/m(2) intravenous cyclophosphamide once per month for 6 months. The primary outcome for all enrolled patients was improvement at 12 months' follow-up, defined as a decrease in mRSS (>25% for those with initial mRSS >14) or an increase in forced vital capacity by more than 10%. Patients in the control group with disease progression (>25% increase in mRSS or decrease of >10% in forced vital capacity) despite treatment with cyclophosphamide could switch to HSCT 12 months after enrolment. This study is registered with ClinicalTrials.gov, number NCT00278525. FINDINGS Between Jan 18, 2006, and Nov 10, 2009 we enrolled 19 patients. All ten patients randomly allocated to receive HSCT improved at or before 12 months' follow-up, compared with none of nine allocated to cyclophosphamide (odds ratio 110, 95% CI 14·04-∞; p=0·00001). Eight of nine controls had disease progression (without interval improvement) compared with no patients treated by HSCT (p=0·0001), and seven patients switched to HSCT. Compared with baseline, data for 11 patients with follow-up to 2 years after HSCT suggested that improvements in mRSS (p<0·0001) and forced vital capacity (p<0·03) persisted. INTERPRETATION Non-myeloablative autologous HSCT improves skin and pulmonary function in patients with systemic sclerosis for up to 2 years and is preferable to the current standard of care, but longer follow-up is needed. FUNDING None.
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Affiliation(s)
- Richard K Burt
- Division of Immunotherapy, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
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Annaloro C, Onida F, Lambertenghi Deliliers G. Autologous hematopoietic stem cell transplantation in autoimmune diseases. Expert Rev Hematol 2011; 2:699-715. [PMID: 21082959 DOI: 10.1586/ehm.09.60] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The term 'autoimmune diseases' encompasses a spectrum of diseases whose clinical manifestations and, possibly, biological features vary widely. The results of conventional treatment are considered unsatisfactory in aggressive forms, with subsets of patients having short life expectancies. Relying on wide experimental evidence and more feeble clinical data, some research groups have used autologous hematopoietic stem cell transplantation (HSCT) in the most disabling autoimmune diseases with the aim of resetting the patient's immune system. Immunoablative conditioning regimens are preferred over their myeloablative counterparts, and some form of in vivo and/or ex vivo T-cell depletion is generally adopted. Despite 15 years' experience, published controlled clinical trials are still lacking, with the evidence so far available coming from pilot studies and registry surveys. In multiple sclerosis, clinical improvement, or at least lasting disease stabilization, can be achieved in the majority of the patients; nevertheless, the worst results are observed in patients with progressive disease, where no benefit can be expected from conventional therapy. Concerning rheumatologic diseases, wide experience has been acquired in systemic sclerosis, with long-term improvements in cutaneous disease being frequently reported, although visceral involvement remains unchanged at best. Autografting has proved to be barely effective in rheumatoid arthritis and quite toxic in juvenile idiopathic arthritis, whereas it leads to clinical remission and the reversal of visceral impairment in the majority of patients with systemic lupus erythematosus. A promising indication is Crohn's disease, in which long-term endoscopic remission is frequently observed. Growing experience with autologous HCST in autoimmune diseases has progressively reduced concerns about transplant-related mortality and secondary myelodysplasia/leukemia. Therefore, a sustained complete remission seems to be within the reach of autografting in some autoimmune diseases; in others, the indications, risks and benefits of autografting need to be better defined. Consequently, the search for new drugs should also be encouraged.
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Affiliation(s)
- Claudio Annaloro
- Bone Marrow Transplantation Center-Hematology I, Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, University of Milan, Via Francesco Sforza 35, Milan, Italy
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Lodi D, Iannitti T, Palmieri B. Stem cells in clinical practice: applications and warnings. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2011; 30:9. [PMID: 21241480 PMCID: PMC3033847 DOI: 10.1186/1756-9966-30-9] [Citation(s) in RCA: 114] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/26/2010] [Accepted: 01/17/2011] [Indexed: 12/11/2022]
Abstract
Stem cells are a relevant source of information about cellular differentiation, molecular processes and tissue homeostasis, but also one of the most putative biological tools to treat degenerative diseases. This review focuses on human stem cells clinical and experimental applications. Our aim is to take a correct view of the available stem cell subtypes and their rational use in the medical area, with a specific focus on their therapeutic benefits and side effects. We have reviewed the main clinical trials dividing them basing on their clinical applications, and taking into account the ethical issue associated with the stem cell therapy.
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Affiliation(s)
- Daniele Lodi
- Department of Nephrology, Dialysis and Transplantation, University of Modena and Reggio Emilia Medical School, Modena, Italy
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Abstract
Systemic scleroderma may serve as a paradigm for orphan diseases where the rarity, different subsets and fluctuating disease activity constitute major obstacles of research into mechanisms and therapeutic development. Recently, significant advances in the detailed understanding of the functioning of growth factors, their receptors and of the physiology of the connective tissue have been achieved. In particular, an improved concept was developed for the pathophysiology of scleroderma, highlighting the role of hypoxia, cellular stress and a concert of interacting cytokines. Tyrosine kinases have been shown to regulate the activity of a number of cytokines and growth factors, e.g. transforming growth factor-beta and platelet-derived growth factor, which play a central role in the pathophysiology of SSc. Novel pharmacological compounds interacting with signalling cascades induced by hypoxia and intracellular signal transduction pathways of mesenchymal cells, e.g. tyrosine kinase inhibitors, are currently being investigated for the treatment of this life-threatening disease.
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50
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Corticosteroids and the risk of scleroderma renal crisis: a systematic review. Rheumatol Int 2010; 32:645-53. [DOI: 10.1007/s00296-010-1697-6] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2010] [Accepted: 11/21/2010] [Indexed: 11/26/2022]
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