|
1
|
Foeldvari I, Torok KS, Silva J, Denton CP, Henes J, Horvei P, Rosser F, Orteu CH, Li SC, Pain CE, Constantin T, Costa-Reis P, Curran ML, Cutolo M, Hinrichs B, Fligelstone K, Maillard S, Moinzadeh P, Pilkington C, Schraven L, Smith V. Guidance for stem cell therapy for juvenile systemic sclerosis patients. Expert Rev Clin Immunol 2025; 21:435-450. [PMID: 40056160 DOI: 10.1080/1744666x.2025.2474216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 02/10/2025] [Accepted: 02/26/2025] [Indexed: 03/10/2025]
Abstract
INTRODUCTION Autologous stem cell transplantation (ASCT) and cellular therapies (CTs) are emerging therapeutic options for both adult and juvenile-onset systemic sclerosis (jSSc) patients. However, most efficacy data are derived from adult studies, and it remains unclear whether adult stem cell transplant criteria are fully applicable to pediatric patients with jSSc. Given pediatric patients' unique potential for recovery and tissue remodeling, the stringent criteria used in adults need adaptation for children. AREAS COVERED We reviewed the current data on indications, patient selection, and outcomes of ASCT and CTs in both adult and pediatric patients with systemic sclerosis. At a multidisciplinary expert workshop held in Hamburg, Germany, in December 2023, we developed consensus guidance on when to consider ASCT and cellular therapies in jSSc. EXPERT OPINION HSCT and CT hold promise as treatment options for jSSc. Our proposed guidance aims to standardize inclusion criteria globally, enhancing comparability of outcomes across future procedures. Establishing consistent inclusion/exclusion criteria and transplant protocols will enable better data collection, interpretation, and ultimately improve outcomes and care for jSSc patients.
Collapse
Affiliation(s)
- Ivan Foeldvari
- Hamburg Centre for Pediatric and Adolescent Rheumatology, Schön Klinik Hamburg Eilbek, Hamburg, Germany
| | - Kathryn S Torok
- University of Pittsburgh School of Medicine and UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | | | | | - Jörg Henes
- Centre for Interdisciplinary Clinical Immunology, Rheumatology and Autoinflammatory Diseases and Department for Internal Medicine II, University Hospital Tübingen, Tübingen, Germany
| | - Paulina Horvei
- University of Pittsburgh School of Medicine and UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Franziska Rosser
- University of Pittsburgh School of Medicine and UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Catherine H Orteu
- UCL Institute of Immunity and Transplantation, Royal Free London NHS Foundation Trust, London, UK
| | - Suzanne C Li
- Joseph M Sanzari Children's Hospital, Hackensack Meridian School of Medicine, Hackensack, NJ, USA
| | - Clare E Pain
- Alder Hey Children's Foundation NHS Trust, Liverpool, UK
| | | | - Patricia Costa-Reis
- Pediatrics Department, Hospital de Santa Maria, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Megan L Curran
- University of Colorado School of Medicine, Aurora, CO, USA
| | - Maurizio Cutolo
- Laboratory of Experimental Rheumatology and Academic Division of Clinical Rheumatology-Department of Internal Medicine and Specialties, University of Genoa and IRCCS San Martino Polyclinic Hospital, Genoa, Italy
| | - Bernd Hinrichs
- Children's pulmonology, Asklepios Klinik Nord - Heidberg, Hamburg, Germany
| | - Kim Fligelstone
- Scleroderma & Raynaud's United Kindgom (SRUK) (Research Subcommittee, Patient Research Partner, FESCA, London, UK
| | | | - Pia Moinzadeh
- Department of Dermatology and Venereology, University Hospital Cologne, Cologne, Germany
| | | | | | - Vanessa Smith
- Department of Internal Medicine, Ghent University, Ghent, Belgium
- Department of Rheumatology, Ghent University Hospital, Ghent, Belgium
- Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center (IRC), Ghent, Belgium
- ERN ReCONNET
| |
Collapse
|
|
2
|
Satirer Ö, Henes JC, Döring M, Lesk T, Benseler S, Kuemmerle-Deschner JB. Autologous haematopoiesis stem cell transplantation (AHSCT) for treatment-refractory autoimmune diseases in children. RMD Open 2024; 10:e004381. [PMID: 39004431 PMCID: PMC11253738 DOI: 10.1136/rmdopen-2024-004381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 06/27/2024] [Indexed: 07/16/2024] Open
Abstract
OBJECTIVES To evaluate the long-term effectiveness and safety of autologous haematopoiesis stem cell transplantation (AHSCT) for severe, refractory autoimmune diseases in paediatric patients. METHODS A single-centre study of consecutive children and adolescents with refractory autoimmune diseases undergoing AHSCT was performed. Demographics, clinical, laboratory features, pre-AHSCT medications, disease activity and functional status were captured. The primary outcome was progression-free survival, secondary outcomes included overall survival, disease-specific treatment responses, disease activity at the last follow-up and AHSCT safety. RESULTS The study included seven patients: two systemic sclerosis, one pansclerotic morphoea, one eosinophilic fasciitis, one juvenile dermatomyositis and two patients with systemic juvenile idiopathic arthritis; four women, three men median age at AHSCT of 10 years (7-19), median follow-up post-AHSCT of 17 years. Median progression-free survival and overall survival was 4.2 years (95% CI: 0.98 to 8.3) and 17 years (95% CI: 11.8 to 22.1), respectively. Progression-free survival rates at 1 and 2 years post-AHSCT were 100% and 77%, respectively. All children survived. All patients are in clinical remission, only four require ongoing immunotherapy. SAFETY Three experienced infections, including HHV6, Candida and Ralstonia sepsis; one developed a systemic inflammatory response syndrome; two new onset secondary autoimmune diseases including autoimmune haemolytic anaemia, Graves' disease and one was found to have a breast fibroadenoma. Treatment toxicity: one cyclophosphamide-associated transient renal failure and pericardial effusion, one patient with amenorrhoea/infertility. CONCLUSIONS AHSCT was an effective and safe approach for children and adolescents with treatment-refractory autoimmune diseases. The indication and timing of transplantation requires a careful consideration and a multidisciplinary approach.
Collapse
Affiliation(s)
- Özlem Satirer
- Department of Paediatrics and Autoinflammation reference Center Tuebingen (arcT), Universitatsklinikum Tubingen, Tubingen, Baden-Württemberg, Germany
| | - Joerg C Henes
- Centre for Interdisciplinary Clinical Immunology, Rheumatology and Auto-inflammatory Diseases and Department of Internal Medicine II (Oncology, Haematology, Immunology and Rheumatology), Universitatsklinikum Tubingen, Tubingen, Baden-Württemberg, Germany
| | - Michaela Döring
- Pediatric Hematology &Oncology, University of Tübingen, Tubingen, Baden-Württemberg, Germany
| | - Till Lesk
- Universitatsklinikum Tubingen, Tubingen, Baden-Württemberg, Germany
| | - Susanne Benseler
- Rheumatology, Alberta Children's Hospital Research Institute, Calgary, Alberta, Canada
- Children's Health Ireland, Dublin, Dublin, Ireland
| | - Jasmin Beate Kuemmerle-Deschner
- Department of Paediatrics and Autoinflammation reference Center Tuebingen (arcT), Universitatsklinikum Tubingen, Tubingen, Baden-Württemberg, Germany
| |
Collapse
|
|
3
|
Foeldvari I, Torok KS, Antón J, Blakley M, Constantin T, Cutolo M, Denton CP, Fligelstone K, Hinrichs B, Li SC, Maillard S, Marrani E, Moinzadeh P, Orteu CH, Pain CE, Pauling JD, Pilkington C, Rosser F, Smith V, Furst DF. Best clinical practice in the treatment of juvenile systemic sclerosis: expert panel guidance - the result of the International Hamburg Consensus Meeting December 2022. Expert Rev Clin Immunol 2024; 20:387-404. [PMID: 38149621 DOI: 10.1080/1744666x.2023.2298354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 12/19/2023] [Indexed: 12/28/2023]
Abstract
INTRODUCTION Juvenile systemic sclerosis (jSSc) is an orphan disease with a prevalence of 3 in 1,000,000 children. Currently there is only one consensus treatment guideline concerning skin, pulmonary and vascular involvement for jSSc, the jSSc SHARE (Single Hub and Access point for pediatric Rheumatology in Europe) initiative, which was based on data procured up to 2014. Therefore, an update of these guidelines, with a more recent literature and expert experience, and extension of the guidance to more aspects of the disease is needed. AREAS COVERED Treatment options were reviewed, and opinions were provided for most facets of jSSc including general management, some of which differs from adult systemic sclerosis, such as the use of corticosteroids, and specific organ involvement, such as skin, musculoskeletal, pulmonary, and gastroenterology. EXPERT OPINION We are suggesting the treat to target strategy to treat early to prevent cumulative disease damage in jSSc. Conclusions are derived from both expert opinion and available literature, which is mostly based on adult systemic sclerosis (aSSc), given shared pathophysiology, extrapolation of results from aSSc studies was judged reasonable.
Collapse
Affiliation(s)
- Ivan Foeldvari
- Hamburg Centre for Pediatric and Adolescent Rheumatology, Schön Klinik Hamburg Eilbek, Hamburg, Germany
| | - Kathryn S Torok
- University of Pittsburgh and University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Jordi Antón
- Department of Pediatric Rheumatology. Hospital Sant Joan de Déu and Universitat de Barcelona, Barcelona, Spain
| | - Michael Blakley
- Riley Hospital for Children at IU Health, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Tamás Constantin
- Unit of Pediatric Rheumatology, Tűzoltó Street Department, Pediatric Centre, Semmelweis University, Budapest, Hungary
| | - Maurizio Cutolo
- Laboratory of Experimental Rheumatology and Academic Division of Clinical Rheumatology-Department of Internal Medicine and Specialties, University of Genoa and IRCCS San Martino Polyclinic Hospital, Genoa, Italy
| | | | - Kim Fligelstone
- Scleroderma & Raynaud's United Kindgom (SRUK) (Research Subcommittee, Patient Research Partner), FESCA, London, UK
| | - Bernd Hinrichs
- Children's pulmonology, Asklepios Klinik Nord - Heidberg, Hamburg, Germany
| | - Suzanne C Li
- Hackensack University Medical Center, Hackensack, NJ, USA
| | | | - Edoardo Marrani
- Pediatric Rheumatology Unit, Meyer Children's Hospital IRCCS, Florence, Italy
| | - Pia Moinzadeh
- Department of Dermatology and Venereology, University Hospital Cologne, Cologne, Germany
| | - Catherine H Orteu
- UCL Institute of Immunity and Transplantation, Royal Free London NHS Foundation Trust, London, UK
| | - Clare E Pain
- Alder Hey Children's Foundation NHS Trust, Liverpool, UK
| | - John D Pauling
- Department of Internal Medicine, Ghent University, Ghent, Belgium
- Department of Rheumatology, Ghent University Hospital, Ghent, Belgium
- Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center (IRC), Ghent, Belgium and ERN ReCONNET
| | | | - Franziska Rosser
- University of Pittsburgh and University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Vanessa Smith
- University of California, Los Angeles, CA, USA
- University of Washington, Seattle, WA, USA
- University of Florence, Florence, Italy
| | - Daniel F Furst
- Division of Rheumatology Fellow, Geffen School of Medicine at the University of California in Los Angeles, Los Angeles, CA, USA
| |
Collapse
|
|
4
|
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.
Collapse
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
| |
Collapse
|
|
5
|
Khanna D, Krieger N, Sullivan KM. Improving outcomes in scleroderma: recent progress of cell-based therapies. Rheumatology (Oxford) 2023; 62:2060-2069. [PMID: 36355455 PMCID: PMC10234204 DOI: 10.1093/rheumatology/keac628] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 10/23/2022] [Indexed: 08/27/2023] Open
Abstract
Scleroderma is a rare, potentially fatal, clinically heterogeneous, systemic autoimmune connective tissue disorder that is characterized by progressive fibrosis of the skin and visceral organs, vasculopathy and immune dysregulation. The more severe form of the disease, diffuse cutaneous scleroderma (dcSSc), has no cure and limited treatment options. Haematopoietic stem cell transplantation has emerged as a potentially disease-modifying treatment but faces challenges such as toxicity associated with fully myeloablative conditioning and recurrence of autoimmunity. Novel cell therapies-such as mesenchymal stem cells, chimeric antigen receptor-based therapy, tolerogenic dendritic cells and facilitating cells-that may restore self-tolerance with more favourable safety and tolerability profiles are being explored for the treatment of dcSSc and other autoimmune diseases. This narrative review examines these evolving cell therapies.
Collapse
Affiliation(s)
- Dinesh Khanna
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Nancy Krieger
- Talaris Therapeutics, Boston, MA and Louisville, KY, USA
| | | |
Collapse
|
|
6
|
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.
Collapse
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
| |
Collapse
|
|
7
|
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.
Collapse
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
| |
Collapse
|
|
8
|
Achini-Gutzwiller FR, Snowden JA, Corbacioglu S, Greco R. Haematopoietic stem cell transplantation for severe autoimmune diseases in children: A review of current literature, registry activity and future directions on behalf of the autoimmune diseases and paediatric diseases working parties of the European Society for Blood and Marrow Transplantation. Br J Haematol 2022; 198:24-45. [PMID: 37655707 DOI: 10.1111/bjh.18176] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 03/14/2022] [Accepted: 03/18/2022] [Indexed: 11/27/2022]
Abstract
Although modern clinical management strategies have improved the outcome of paediatric patients with severe autoimmune and inflammatory diseases over recent decades, a proportion will experience ongoing or recurrent/relapsing disease activity despite multiple therapies often leading to irreversible organ damage, and compromised quality of life, growth/development and long-term survival. Autologous and allogeneic haematopoietic stem cell transplantation (HSCT) have been used successfully to induce disease control and often apparent cure of severe treatment-refractory autoimmune diseases (ADs) in children. However, transplant-related outcomes are disease-dependent and long-term outcome data are limited in respect to efficacy and safety. Moreover, balancing risks of HSCT against AD prognosis with continually evolving non-transplant options is challenging. This review appraises published literature on HSCT strategies and outcomes in individual paediatric ADs. We also provide a summary of the European Society for Blood and Marrow Transplantation (EBMT) Registry, where 343 HSCT procedures (176 autologous and 167 allogeneic) have been reported in 326 children (<18 years) for a range of AD indications. HSCT is a promising treatment modality, with potential long-term disease control or cure, but therapy-related morbidity and mortality need to be reduced. Further research is warranted to establish the position of HSCT in paediatric ADs via registries and prospective clinical studies to support evidence-based interspeciality guidelines and recommendations.
Collapse
Affiliation(s)
- Federica R Achini-Gutzwiller
- Division of Paediatric Stem Cell Transplantation and Haematology, Children's Research Centre (CRC), University Children's Hospital of Zurich, Zurich, Switzerland
| | - John A Snowden
- Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield, UK
| | - Selim Corbacioglu
- Department of Paediatric Oncology, Haematology and Stem Cell Transplantation, University Children's Hospital Regensburg, Regensburg, Germany
| | - Raffaella Greco
- Unit of Haematology and Bone Marrow Transplantation, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
| |
Collapse
|
|
9
|
Papadimitriou TI, van Caam A, van der Kraan PM, Thurlings RM. Therapeutic Options for Systemic Sclerosis: Current and Future Perspectives in Tackling Immune-Mediated Fibrosis. Biomedicines 2022; 10:316. [PMID: 35203525 PMCID: PMC8869277 DOI: 10.3390/biomedicines10020316] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/21/2022] [Accepted: 01/26/2022] [Indexed: 02/01/2023] Open
Abstract
Systemic sclerosis (SSc) is a severe auto-immune, rheumatic disease, characterized by excessive fibrosis of the skin and visceral organs. SSc is accompanied by high morbidity and mortality rates, and unfortunately, few disease-modifying therapies are currently available. Inflammation, vasculopathy, and fibrosis are the key hallmarks of SSc pathology. In this narrative review, we examine the relationship between inflammation and fibrosis and provide an overview of the efficacy of current and novel treatment options in diminishing SSc-related fibrosis based on selected clinical trials. To do this, we first discuss inflammatory pathways of both the innate and acquired immune systems that are associated with SSc pathophysiology. Secondly, we review evidence supporting the use of first-line therapies in SSc patients. In addition, T cell-, B cell-, and cytokine-specific treatments that have been utilized in SSc are explored. Finally, the potential effectiveness of tyrosine kinase inhibitors and other novel therapeutic approaches in reducing fibrosis is highlighted.
Collapse
Affiliation(s)
- Theodoros-Ioannis Papadimitriou
- Department of Rheumatic Diseases, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; (A.v.C.); (P.M.v.d.K.); (R.M.T.)
| | | | | | | |
Collapse
|
|
10
|
Yoshimi R, Nakajima H. Current State and Issues of Regenerative Medicine for Rheumatic Diseases. Front Med (Lausanne) 2022; 9:813952. [PMID: 35155499 PMCID: PMC8831787 DOI: 10.3389/fmed.2022.813952] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 01/05/2022] [Indexed: 12/15/2022] Open
Abstract
The prognosis of rheumatic diseases is generally better than that of malignant diseases. However, some cases with poor prognoses resist conventional therapies and cause irreversible functional and organ damage. In recent years, there has been much research on regenerative medicine, which uses stem cells to restore the function of missing or dysfunctional tissues and organs. The development of regenerative medicine is also being attempted in rheumatic diseases. In diseases such as systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and rheumatoid arthritis, hematopoietic stem cell transplantation has been attempted to correct and reconstruct abnormalities in the immune system. Mesenchymal stem cells (MSCs) have also been tried for the treatment of refractory skin ulcers in SSc using the ability of MSCs to differentiate into vascular endothelial cells and for the treatment of systemic lupus erythematosus SLE using the immunosuppressive effect of MSCs. CD34-positive endothelial progenitor cells (EPCs), which are found in the mononuclear cell fraction of bone marrow and peripheral blood, can differentiate into vascular endothelial cells at the site of ischemia. Therefore, EPCs have been used in research on vascular regeneration therapy for patients with severe lower limb ischemia caused by rheumatic diseases such as SSc. Since the first report of induced pluripotent stem cells (iPSCs) in 2007, research on regenerative medicine using iPSCs has been actively conducted, and their application to rheumatic diseases is expected. However, there are many safety issues and bioethical issues involved in regenerative medicine research, and it is essential to resolve these issues for practical application and spread of regenerative medicine in the future. The environment surrounding regenerative medicine research is changing drastically, and the required expertise is becoming higher. This paper outlines the current status and challenges of regenerative medicine in rheumatic diseases.
Collapse
|
|
11
|
El-Kadiry AEH, Rafei M, Shammaa R. Cell Therapy: Types, Regulation, and Clinical Benefits. Front Med (Lausanne) 2021; 8:756029. [PMID: 34881261 PMCID: PMC8645794 DOI: 10.3389/fmed.2021.756029] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 11/01/2021] [Indexed: 12/12/2022] Open
Abstract
Cell therapy practices date back to the 19th century and continue to expand on investigational and investment grounds. Cell therapy includes stem cell- and non-stem cell-based, unicellular and multicellular therapies, with different immunophenotypic profiles, isolation techniques, mechanisms of action, and regulatory levels. Following the steps of their predecessor cell therapies that have become established or commercialized, investigational and premarket approval-exempt cell therapies continue to provide patients with promising therapeutic benefits in different disease areas. In this review article, we delineate the vast types of cell therapy, including stem cell-based and non-stem cell-based cell therapies, and create the first-in-literature compilation of the different "multicellular" therapies used in clinical settings. Besides providing the nuts and bolts of FDA policies regulating their use, we discuss the benefits of cell therapies reported in 3 therapeutic areas-regenerative medicine, immune diseases, and cancer. Finally, we contemplate the recent attention shift toward combined therapy approaches, highlighting the factors that render multicellular therapies a more attractive option than their unicellular counterparts.
Collapse
Affiliation(s)
- Abed El-Hakim El-Kadiry
- Laboratory of Thrombosis and Hemostasis, Montreal Heart Institute, Research Center, Montreal, QC, Canada
- Department of Biomedical Sciences, Université de Montréal, Montreal, QC, Canada
| | - Moutih Rafei
- Department of Pharmacology and Physiology, Université de Montréal, Montreal, QC, Canada
- Department of Microbiology, Infectious Diseases and Immunology, Université de Montréal, Montreal, QC, Canada
- Molecular Biology Program, Université de Montréal, Montreal, QC, Canada
- Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada
| | - Riam Shammaa
- Canadian Centre for Regenerative Therapy, Toronto, ON, Canada
- Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada
| |
Collapse
|
|
12
|
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.
Collapse
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
| |
Collapse
|
|
13
|
Abinun M, Slatter MA. Haematopoietic stem cell transplantation in paediatric rheumatic disease. Curr Opin Rheumatol 2021; 33:387-397. [PMID: 34261117 DOI: 10.1097/bor.0000000000000823] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
PURPOSE OF REVIEW A small proportion of children affected by rheumatic diseases suffer from severe, progressive disease, resistant to conventional antirheumatic therapies and to biologic agents interfering with inflammatory cytokines, costimulatory molecules expressed on immune system cells and intracellular signalling pathways. Adding to the poor prognosis is a high risk from significant morbidity and mortality associated with long-term treatment with multiple, often combined anti-inflammatory and immunosuppressive agents. Carefully selected patients from this unfortunate group may benefit from treatment with haematopoietic stem cell transplantation. RECENT FINDINGS The majority of patients with severe paediatric rheumatic and autoinflammatory diseases treated with autologous and/or allogeneic haematopoietic stem cell transplantation achieved long-term remission. However, the incidence of disease relapse and transplant related morbidity and mortality is still significant. SUMMARY Careful patient and donor selection, timing of the transplant earlier in the course of disease rather than the 'last resort' and choosing the most suitable conditioning regimen for each individual patient are the major factors favouring successful outcome. Close co-operation between the patients, their family, and involved medical teams is essential.
Collapse
Affiliation(s)
- Mario Abinun
- Department of Paediatric Immunology, Great North Children's Hospital, Newcastle upon Tyne Hospitals National Health Service Foundation Trust, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University
| | - Mary A Slatter
- Haematopoietic Stem Cell Transplantation Unit, Great North Children's Hospital, Newcastle upon Tyne Hospitals, National Health Service Foundation Trust, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| |
Collapse
|
|
14
|
Spierings J, Chiu YH, Voortman M, van Laar JM. Autologous stem-cell transplantation in systemic sclerosis-associated interstitial lung disease: early action in selected patients rather than escalation therapy for all. Ther Adv Musculoskelet Dis 2021; 13:1759720X211035196. [PMID: 34394749 PMCID: PMC8361525 DOI: 10.1177/1759720x211035196] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 07/07/2021] [Indexed: 12/29/2022] Open
Abstract
Systemic sclerosis (SSc) is a rare rheumatic disease characterised by inflammation, vasculopathy and fibrosis of skin and internal organs. A common complication and a leading cause of death in SSc is interstitial lung disease (ILD). The current armamentarium of treatments in SSc-ILD mainly includes immunosuppressive therapies and has recently been expanded with anti-fibrotic agent nintedanib. Autologous stem cell transplantation (SCT) is increasingly used in progressive diffuse cutaneous SSc. This intensive treatment has been studied in three randomised trials and demonstrated to improve survival and quality of life. In the subsets of patients with SSc-ILD, SCT resulted in stabilisation and modest improvement of lung volumes and disease extent on high resolution computed tomography, but less impact was seen on diffusion capacity. Comparison of SCT outcomes with results from SSc-ILD trials is difficult though, as lung involvement per se was not an inclusion criterion in all SCT trials. Also, baseline characteristics differed between studies. The risk of severe treatment-related complications from SCT is still considerable and patients with extensive lung disease are particularly at risk of complications during transplantation. Therefore SCT should only be provided by experienced multidisciplinary teams in carefully selected patients. Future research needs to include comprehensive pulmonary evaluation and establish whether SCT early in the disease might prevent irreversible pulmonary damage and reduce treatment-related complications. Also, more insight in mechanisms of action of SCT in the lung and predictors for response will improve the use of this treatment in SSc-ILD. In this review the role of SCT in the treatment of SSc-ILD is summarised.
Collapse
Affiliation(s)
- J. Spierings
- Department of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, Heidelberglaan 100, Utrecht, 3584 CX, the Netherlands
- Division of Medicine, Department of Inflammation, Centre for Rheumatology and Connective Tissue Diseases, Royal Free and University College Medical School, University College London, London, UK
| | - Y-H. Chiu
- Department of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, Utrecht, the Netherlands
- Division of Rheumatology/Immunology/Allergy, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei
| | - M. Voortman
- Department of Pulmonology, Division of Heart and Lungs, University Medical Centre Utrecht, Utrecht, the Netherlands
| | - J. M. van Laar
- Department of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, Utrecht, the Netherlands
| |
Collapse
|
|
15
|
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.
Collapse
|
|
16
|
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.
Collapse
Affiliation(s)
- Mary Karin Connolly
- Department of Dermatology, University of California, San Francisco, San Francisco, CA 94115, USA
| |
Collapse
|
|
17
|
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.
Collapse
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.
| |
Collapse
|
|
18
|
AlOdhaibi KA, Varga J, Furst DE. Hematopoietic stem cell transplantation in systemic sclerosis: Yes!! BUT. . JOURNAL OF SCLERODERMA AND RELATED DISORDERS 2021; 6:44-49. [PMID: 35382253 PMCID: PMC8922628 DOI: 10.1177/2397198320971967] [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: 04/23/2020] [Accepted: 10/18/2020] [Indexed: 12/12/2023]
Abstract
Systemic sclerosis is a chronic multisystem, autoimmune disease with high mortality, and to date, has no effective approved therapy. For patients with the most severe forms of systemic sclerosis, autologous hematopoietic stem cell therapy has been proven to be effective, as demonstrated by three randomized controlled clinical trials and at least two registry studies. In the controlled studies, autologous hematopoietic stem cell therapy was shown to improve mortality, skin involvement, quality-of-life, and function compared with patients treated with intravenous cyclophosphamide. There is significant transplant-related mortality associated with autologous hematopoietic stem cell therapy, as well as infectious and noninfectious serious adverse events, including cardiac and renal compromise. Although the results of autologous hematopoietic stem cell therapy clinical trials to date are highly encouraging, a number of important unanswered questions remain. These include the following: What is the optimal transplant regimen; can the spectrum of systemic sclerosis patients who respond to autologous hematopoietic stem cell therapy be expanded; how can disease relapse following autologous hematopoietic stem cell therapy be predicted and managed; can treatment-related toxicity and mortality be mitigated; can response or toxicity be predicted; and finally, is there a place for allogeneic stem cell transplants in systemic sclerosis? Systemic sclerosis is an autoimmune disease with multiple immunological, vascular, and fibrotic abnormalities. Immunosuppressive therapy is frequently used, but to date its efficacy has been generally modest. Stem cell transplantation is the most potent immunosuppressive therapy currently available, and as discussed below, may have an important role in the management of systemic sclerosis.
Collapse
Affiliation(s)
| | - John Varga
- University of Michigan, Ann Arbor, MI, USA
| | - Daniel E Furst
- University of California-Los Angeles, Los Angeles, CA, USA
- University of Washington, Seattle, WA, USA
- University of Florence, Florence, Italy
| |
Collapse
|
|
19
|
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.
Collapse
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
| | | |
Collapse
|
|
20
|
Riemekasten G, Petersen F, Heidecke H. What Makes Antibodies Against G Protein-Coupled Receptors so Special? A Novel Concept to Understand Chronic Diseases. Front Immunol 2020; 11:564526. [PMID: 33384684 PMCID: PMC7770155 DOI: 10.3389/fimmu.2020.564526] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 11/13/2020] [Indexed: 12/13/2022] Open
Abstract
Expressions of G protein-coupled receptors (GPCR) on immune and tissue resident cells are the consequence of the cellular environment, which is highly variable. As discussed here, antibodies directed to GPCR (GPCR abs), their levels and correlations to other abs, serve as biomarkers for various diseases. They also could reflect the individual interplay between the environment and the immune system. Thus, GPCR abs could display pathogenic chronic conditions and could help to identify disease-related pathways. Moreover, by acting as ligands to their corresponding receptors, GPCR abs modulate autoimmune as well as non-autoimmune diseases. This article introduces GPCR abs as drivers for diseases by their capability to induce a specific signaling and by determining immune cell homeostasis. The identification of the individual GPCR ab function is challenging but might be pivotal in the comprehension of the aetiology of diseases. This, hopefully, will lead to the identification of novel therapeutic strategies. This article provides an overview about concepts and recent developments in research. Accordingly, GPCR abs could represent ideal candidates for precision medicine. Here, we introduce the term antibodiom to cover the network of abs with GPCR abs as prominent players.
Collapse
Affiliation(s)
- Gabriela Riemekasten
- Clinic of Rheumatology and Clinical Immunology, University Hospital Schleswig-Holstein, University of Lübeck, Lübeck, Germany
- Research Center Borstel, Division of Pulmonary Immune Diseases, Member of the German Center for Lung Research (DZL), Borstel, Germany
- Research Center Borstel, Member of the German Center for Lung Research (DZL), Borstel, Germany
- Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Borstel, Germany
| | - Frank Petersen
- Research Center Borstel, Division of Pulmonary Immune Diseases, Member of the German Center for Lung Research (DZL), Borstel, Germany
- Research Center Borstel, Member of the German Center for Lung Research (DZL), Borstel, Germany
- Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Borstel, Germany
| | | |
Collapse
|
|
21
|
Fallet B, Walker UA. Current immunosuppressive and antifibrotic therapies of systemic sclerosis and emerging therapeutic strategies. Expert Rev Clin Pharmacol 2020; 13:1203-1218. [PMID: 33008265 DOI: 10.1080/17512433.2020.1832466] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
INTRODUCTION Systemic sclerosis (SSc) is a rare, difficult to treat disease with profound effects on quality of life and high mortality. Complex and incompletely understood pathophysiologic processes and greatly heterogeneous clinical presentations and outcomes have hampered drug development. AREAS COVERED This review summarizes the currently available immunosuppressive and antifibrotic therapies and discusses novel approaches for the treatment of SSc. We reviewed the literature using the MEDLINE and ClinicalTrial.gov databases between May and September 2020. EXPERT OPINION Available immunosuppressive and antifibrotic drugs only modestly impact the course of the disease. Most drugs are currently only investigated in the subset of patients with early diffuse cutaneous SSc. In this patient population, hematopoietic stem-cell transplantation is currently the only treatment that has demonstrated reversal of lung involvement, enhanced quality of life and reduced long-term mortality, but carries the risk of short-term treatment-related mortality. A great need to provide better therapeutic options to patients exists also for those patients who have limited cutaneous skin involvement. A better understanding of SSc pathophysiology has enabled the identification of numerous new therapeutic targets. The progress made in the design of clinical trials and outcome parameters will likely result in the improvement of effective management options.
Collapse
Affiliation(s)
- Bénédict Fallet
- Department of Rheumatology, University Hospital Basel , Basel, Switzerland
| | - Ulrich A Walker
- Department of Rheumatology, University Hospital Basel , Basel, Switzerland
| |
Collapse
|
|
22
|
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.
Collapse
|
|
23
|
Hawsawi YM, Al-Zahrani F, Mavromatis CH, Baghdadi MA, Saggu S, Oyouni AAA. Stem Cell Applications for Treatment of Cancer and Autoimmune Diseases: Its Promises, Obstacles, and Future Perspectives. Technol Cancer Res Treat 2019; 17:1533033818806910. [PMID: 30343639 PMCID: PMC6198389 DOI: 10.1177/1533033818806910] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Since the original discovery of stem cells, a new era of promising results has emerged in the clinical application of stem cells for the treatment of several important diseases, including cancer and autoimmune diseases. The plentiful research on stem cells during the past decades has provided significant information on the developmental, morphological, and physiological processes that govern tissue and organ formation, maintenance, and regeneration; cellular differentiation; molecular processes; and tissue homeostasis. In this review, we present the history of the use of stem cells in different clinical applications. Furthermore, we discuss the various therapeutic options for stem cells in cancer, followed by the role of stem cells in the treatment of autoimmune disorders. Additionally, we highlight the risks of and obstacles to the application of stem cells in clinical practice. Ultimately, we show future perspectives in stem cell use, with an aim to improve the clinical usefulness of stem cells.
Collapse
Affiliation(s)
- Yousef M Hawsawi
- 1 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia.,2 Department of Biological Sciences, Faculty of Science and Arts, King Abdulaziz University, Rabigh, Kingdom of Saudi Arabia.,3 Department of Epidemiology and Biostatistics, King Faisal Specialist Hospital and Research Center, Jeddah, Kingdom of Saudi Arabia
| | - Faisal Al-Zahrani
- 2 Department of Biological Sciences, Faculty of Science and Arts, King Abdulaziz University, Rabigh, Kingdom of Saudi Arabia
| | - Charalampos Harris Mavromatis
- 2 Department of Biological Sciences, Faculty of Science and Arts, King Abdulaziz University, Rabigh, Kingdom of Saudi Arabia
| | - Mohammed A Baghdadi
- 1 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia.,3 Department of Epidemiology and Biostatistics, King Faisal Specialist Hospital and Research Center, Jeddah, Kingdom of Saudi Arabia
| | - Shalini Saggu
- 4 Department of Biology, Faculty of Sciences, University of Tabuk, Tabuk, Kingdom of Saudi Arabia
| | - Atif Abdulwahab A Oyouni
- 4 Department of Biology, Faculty of Sciences, University of Tabuk, Tabuk, Kingdom of Saudi Arabia
| |
Collapse
|
|
24
|
Das A, Kumar A, Arrossi AV, Ghosh S, Highland KB. Scleroderma-related interstitial lung disease: principles of management. Expert Rev Respir Med 2019; 13:357-367. [PMID: 30686069 DOI: 10.1080/17476348.2019.1575732] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
INTRODUCTION Interstitial lung disease (ILD) is the most common cause of mortality in systemic sclerosis; accounting for approximately 35% of deaths. Although immunosuppression is currently opted as first line therapy for scleroderma-related ILD (SSc-ILD), the benefits from it remain modest with concerns for systemic toxicity from long term use. Areas covered: We review the important facets in monitoring a patient with SSc-ILD, including recognizing various patterns of ILD, identifying those at risk for disease progression and discuss the strength of evidence for immunosuppressant drugs and lung transplantation. We also discuss the potential role of anti-fibrotic agents and the existing evidence for myeloablative stem-cell transplantation. Expert commentary: Non-specific interstitial pneumonia (NSIP) is the most common radiologic and histopathologic pattern seen, but other forms of ILD may also be appreciated. Mycophenolate mofetil and cyclophosphamide are most commonly used as first line therapy for SSc-ILD; however, the efficacy of mycophenolate is comparable to cyclophosphamide with a better tolerability profile. Selected patients with SSc-ILD may be candidates for lung transplantation, although meticulous assessment for co-morbidities is crucial. Further studies are required to deduce the role of anti-fibrotic medications, biologic agents and effects of myeloablative stem cell transplantation in SSc.
Collapse
Affiliation(s)
- Aparna Das
- a Division of Internal Medicine , Spectrum Health-Michigan State University College of Human Medicine , Grand Rapids , MI , USA
| | - Anupam Kumar
- b Division of Pulmonary & Critical Care Medicine , Richard DeVos Heart & Lung Transplant Program , Grand Rapids , MI , USA
| | | | - Subha Ghosh
- d Radiology Institute , Cleveland Clinic , Cleveland , OH , USA
| | | |
Collapse
|
|
25
|
Ayano M, Tsukamoto H, Mitoma H, Kimoto Y, Akahoshi M, Arinobu Y, Miyamoto T, Horiuchi T, Niiro H, Nagafuji K, Harada M, Akashi K. CD34-selected versus unmanipulated autologous haematopoietic stem cell transplantation in the treatment of severe systemic sclerosis: a post hoc analysis of a phase I/II clinical trial conducted in Japan. Arthritis Res Ther 2019; 21:30. [PMID: 30670057 PMCID: PMC6341635 DOI: 10.1186/s13075-019-1823-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Accepted: 01/14/2019] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND The effectiveness of autologous haematopoietic stem cell transplantation (auto-HSCT) in treating severe systemic sclerosis (SSc) is established; however, the necessity of purified CD34+ cell grafts and the appropriate conditioning regimen remain unclear. This study aimed to compare the efficacy and safety of CD34-selected auto-HSCT with unmanipulated auto-HSCT to treat severe SSc. METHODS This study was a post hoc analysis of a phase I/II clinical trial conducted in Japan. Nineteen patients with severe SSc were enrolled. Peripheral blood stem cells (PBSCs) were mobilised with cyclophosphamide (4 g/m2) and filgrastim (10 μg/kg/day). Following PBSC collection by apheresis, CD34+ cells were immunologically selected in 11 patients. All patients were treated with high-dose cyclophosphamide (200 mg/kg) monotherapy as a conditioning regimen and received CD34-selected (n = 11) or unmanipulated auto-HSCT (n = 8). Changes in skin sclerosis and pulmonary function were assessed over an 8-year follow-up period. Differences in the changes, toxicity, progression-free survival (PFS) and overall survival were compared between patients who had received CD34-selected auto-HSCT and those who had received unmanipulated auto-HSCT. RESULTS Skin sclerosis progressively improved after transplantation over an 8-year follow-up period in both groups, and the improvement was significantly greater in the CD34-selected group than in the unmanipulated group. Forced vital capacity in the CD34-selected group continuously increased over 8 years, whereas in the unmanipulated group it returned to baseline 3 years after transplantation. Toxicity and viral infections, such as cytomegalovirus infection and herpes zoster, were more frequently found in the CD34-selected group than in the unmanipulated group. The frequency of severe adverse events, such as bacterial infections or organ toxicity, was similar between the two groups. No treatment-related deaths occurred in either treatment group. PFS of the CD34-selected group was greater than that of the unmanipulated group, and the 5-year PFS rates of the CD34-selected and unmanipulated group were 81.8% and 50% respectively. CONCLUSIONS CD34-selected auto-HSCT may produce favourable effects on improvement of skin sclerosis and pulmonary function compared with unmanipulated auto-HSCT. Use of CD34-selected auto-HSCT with high-dose cyclophosphamide monotherapy as a conditioning regimen may offer an excellent benefit-to-risk balance.
Collapse
Affiliation(s)
- Masahiro Ayano
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. .,Department of Cancer Stem Cell Research, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
| | - Hiroshi Tsukamoto
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.,Present Address: Department of Rheumatology, Shin-Kokura Hospital, 1-3-1 Kanada, Kokurakita-ku, Kitakyushu, 803-8505, Japan
| | - Hiroki Mitoma
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yasutaka Kimoto
- Department of Internal Medicine, Kyushu University Beppu Hospital, 4546 Tsurumibaru, Tsurumi, Beppu, 874-0838, Japan
| | - Mitsuteru Akahoshi
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yojiro Arinobu
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Toshihiro Miyamoto
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Takahiko Horiuchi
- Department of Internal Medicine, Kyushu University Beppu Hospital, 4546 Tsurumibaru, Tsurumi, Beppu, 874-0838, Japan
| | - Hiroaki Niiro
- Department of Medical Education, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Koji Nagafuji
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.,Present Address: Division of Hematology and Oncology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan
| | - Mine Harada
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.,Present Address: Medical Center for Karatsu-Higashimatsuura Medical Association, 2566-11 Chiyoda-machi, Karatsu, 847-0041, Japan
| | - Koichi Akashi
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| |
Collapse
|
|
26
|
Richeldi L, Varone F, Bergna M, de Andrade J, Falk J, Hallowell R, Jouneau S, Kondoh Y, Morrow L, Randerath W, Strek M, Tabaj G. Pharmacological management of progressive-fibrosing interstitial lung diseases: a review of the current evidence. Eur Respir Rev 2018; 27:27/150/180074. [PMID: 30578333 PMCID: PMC9488647 DOI: 10.1183/16000617.0074-2018] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 10/30/2018] [Indexed: 12/21/2022] Open
Abstract
A proportion of patients with interstitial lung diseases (ILDs) are at risk of developing a progressive-fibrosing phenotype, which is associated with a deterioration in lung function and early mortality. In addition to idiopathic pulmonary fibrosis (IPF), fibrosing ILDs that may present a progressive phenotype include idiopathic nonspecific interstitial pneumonia, connective tissue disease-associated ILDs, hypersensitivity pneumonitis, unclassifiable idiopathic interstitial pneumonia, ILDs related to other occupational exposures and sarcoidosis. Corticosteroids and/or immunosuppressive therapies are sometimes prescribed to patients with these diseases. However, this treatment regimen may not be effective, adequate on its own or well tolerated, suggesting that there is a pressing need for efficacious and better tolerated therapies. Currently, the only approved treatments to slow disease progression in patients with IPF are nintedanib and pirfenidone. Similarities in pathobiological mechanisms leading to fibrosis between IPF and other ILDs that may present a progressive-fibrosing phenotype provide a rationale to suggest that nintedanib and pirfenidone may be therapeutic options for patients with the latter diseases. This review provides an overview of the therapeutic options currently available for patients with fibrosing ILDs, including fibrosing ILDs that may present a progressive phenotype, and explores the status of the randomised controlled trials that are underway to determine the efficacy and safety of nintedanib and pirfenidone. Aside from IPF, there are no proven therapies for other ILDs with a progressive-fibrosing phenotype that are effective and have tolerable adverse effects. Clinical studies evaluating the benefits of antifibrotic therapy in these populations are underway.http://ow.ly/40yL30mOs0q
Collapse
Affiliation(s)
- Luca Richeldi
- Unità Operativa Complessa di Pneumologia, Fondazione Policlinico Universitario A. Gemelli IRCSS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Francesco Varone
- Unità Operativa Complessa di Pneumologia, Fondazione Policlinico Universitario A. Gemelli IRCSS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Miguel Bergna
- Centro Médico de Enfermedades, Respiratorias, Florida, Vicente López, Buenos Aires, Argentina
| | | | - Jeremy Falk
- Cedars-Sinai Medical Center, Division of Pulmonary and Critical Care Medicine, Los Angeles, CA, USA
| | - Robert Hallowell
- Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Stéphane Jouneau
- Respiratory Diseases Dept, Hôpital Pontchaillou, IRSET, Université de Rennes 1, Rennes, France
| | - Yasuhiro Kondoh
- Dept of Respiratory Medicine and Allergy, Tosei General Hospital, Seto, Japan
| | - Lee Morrow
- Division of Pulmonary, Critical Care and Sleep Medicine, Dept of Internal Medicine, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, USA
| | - Winfried Randerath
- Institute of Pneumology, University of Cologne, Bethanien Hospital, Solingen, Germany
| | - Mary Strek
- Dept of Radiology, University of Chicago, Chicago, IL, USA
| | - Gabriela Tabaj
- Pulmonary Medicine, Cetrángolo Hospital, Buenos Aires, Argentina
| |
Collapse
|
|
27
|
|
|
28
|
Del Papa N, Pignataro F, Zaccara E, Maglione W, Minniti A. Autologous Hematopoietic Stem Cell Transplantation for Treatment of Systemic Sclerosis. Front Immunol 2018; 9:2390. [PMID: 30386340 PMCID: PMC6198074 DOI: 10.3389/fimmu.2018.02390] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 09/26/2018] [Indexed: 12/29/2022] Open
Abstract
Systemic Sclerosis (SSc) is a complex autoimmune disease, characterized by high mortality and morbidity. The heterogeneity in terms of extent, severity, and rate of progression of skin and internal organ involvement gives rise to many difficulties in finding the optimal therapeutic interventions for SSc and, to date, no disease-modifying agents are available. In this scenario, it is not surprising that SSc was one of the first autoimmune diseases challenged with high-dose immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (AHSCT). In the last decades, AHSCT has emerged as a treatment option for refractory SSc through a reduction of the aberrant immune cells, followed by re-constitution of a new, self-tolerant immune system. After several case series and pilot studies, more recently three randomized controlled trials have shown a benefit in skin involvement, organ functions and quality of life measures in AHSCT compared to monthly cyclophosphamide. In addition, although AHSCT presents a certain risk of mortality, it has been shown that the overall survival is better, compared to the cyclophosphamide group. Current evidence suggests that SSc patients who are most likely to benefit from AHSCT are early, active, with rapidly progressing diffuse skin disease, and mild involvement of internal organs. As the studies have progressed, it has become evident the need for a more rigorous patient selection, the optimization of transplant and post-transplant procedures, and the intervention of multidisciplinary teams of specialists to increase the safety and efficacy of AHSCT in SSc.
Collapse
Affiliation(s)
- Nicoletta Del Papa
- Dipartimento di Fisiatria e Reumatologia, Istituto Ortopedico Gaetano Pini, Milan, Italy
| | - Francesca Pignataro
- Dipartimento di Fisiatria e Reumatologia, Istituto Ortopedico Gaetano Pini, Milan, Italy
| | - Eleonora Zaccara
- Dipartimento di Fisiatria e Reumatologia, Istituto Ortopedico Gaetano Pini, Milan, Italy
| | - Wanda Maglione
- Dipartimento di Fisiatria e Reumatologia, Istituto Ortopedico Gaetano Pini, Milan, Italy
| | - Antonina Minniti
- Dipartimento di Fisiatria e Reumatologia, Istituto Ortopedico Gaetano Pini, Milan, Italy
| |
Collapse
|
|
29
|
Touré SB, Kleiderman E, Knoppers BM. Bridging stem cell research and medicine: a learning health system. Regen Med 2018; 13:741-752. [PMID: 30043682 DOI: 10.2217/rme-2017-0129] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Stem cells may not systematically obey traditional Phase I-IV clinical translation models. In response, various actors have suggested that stem cell-based medical innovation models could catalyze translation instead. Accordingly, calls were made to adopt more permissive approaches to stem cell translation. Yet, the Phase I-IV paradigm remains the standard within the scientific community. This article seeks to advance the stalemated discussions by proposing an alternative model for consideration. In it, we argue that a stem cell-based learning health system may be able to reconcile these two models. Centered on the acceleration of evidence and knowledge flow, a stem cell-based learning health system could maximize patient retention and data follow-up, thereby promoting inclusive system learning and improvement.
Collapse
Affiliation(s)
- Seydina B Touré
- Centre of Genomics & Policy, Department of Human Genetics, McGill University, Montréal, QC H3A 0G1, Canada
| | - Erika Kleiderman
- Centre of Genomics & Policy, Department of Human Genetics, McGill University, Montréal, QC H3A 0G1, Canada
| | - Bartha M Knoppers
- Centre of Genomics & Policy, Department of Human Genetics, McGill University, Montréal, QC H3A 0G1, Canada
| |
Collapse
|
|
30
|
Walker UA, Saketkoo LA, Distler O. Haematopoietic stem cell transplantation in systemic sclerosis. RMD Open 2018; 4:e000533. [PMID: 30018796 PMCID: PMC6045702 DOI: 10.1136/rmdopen-2017-000533] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 05/23/2018] [Accepted: 06/04/2018] [Indexed: 12/29/2022] Open
Abstract
Three randomised controlled trials of haematopoietic stem cell transplantation (HSCT) in systemic sclerosis (SSc) demonstrated long-term survival benefits, induction of clinically meaningful, sustained improvement of forced vital capacity with improvements in skin thickening, vasculopathy and health-related quality of life, in contrast to a clinical decline in standard of care control groups. These benefits, however, must be weighed against the increased risk of transplant-related mortality. Further, with disease progression, severe extensive internal organ involvement and damage ensues, constituting an exclusion criterion for safety reasons, leaving a limited window whereby patients with SSc are eligible for HSCT. Although autologous HSCT offers the possibility of drug-free remission, relapse can occur, requiring re-initiation of disease modifying antirheumatic drugs. HSCT is also associated with secondary autoimmune diseases and gonadal failure. HSCT should be proposed for carefully selected patients with early rapidly progressive diffuse SSc whose clinical picture portends a poor prognosis for survival, but yet lacks advanced organ involvement.
Collapse
Affiliation(s)
- Ulrich A Walker
- Department of Rheumatology, University Hospital Basel, Basel, Switzerland
| | - Lesley Ann Saketkoo
- Tulane University School of Medicine Lung Center, New Orleans Scleroderma and Sarcoidosis Patient Care and Research Center, University Medical Center - Comprehensive Pulmonary Hypertension Center, New Orleans, Louisiana, USA
| | - Oliver Distler
- Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland
| |
Collapse
|
|
31
|
Asano Y, Jinnin M, Kawaguchi Y, Kuwana M, Goto D, Sato S, Takehara K, Hatano M, Fujimoto M, Mugii N, Ihn H. Diagnostic criteria, severity classification and guidelines of systemic sclerosis. J Dermatol 2018; 45:633-691. [PMID: 29687465 DOI: 10.1111/1346-8138.14162] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 11/06/2017] [Indexed: 01/17/2023]
Abstract
Several effective drugs have been identified for the treatment of systemic sclerosis (SSc). However, in advanced cases, not only their effectiveness is reduced but they may be also harmful due to their side-effects. Therefore, early diagnosis and early treatment is most important for the treatment of SSc. We established diagnostic criteria for SSc in 2003 and early diagnostic criteria for SSc in 2011, for the purpose of developing evaluation of each organ in SSc. Moreover, in November 2013, the American College of Rheumatology and the European Rheumatology Association jointly developed new diagnostic criteria for increasing their sensitivity and specificity, so we revised our diagnostic criteria and severity classification of SSc. Furthermore, we have revised the clinical guideline based on the newest evidence. In particular, the clinical guideline was established by clinical questions based on evidence-based medicine according to the New Minds Clinical Practice Guideline Creation Manual (version 1.0). We aimed to make the guideline easy to use and reliable based on the newest evidence, and to present guidance as specific as possible for various clinical problems in treatment of SSc.
Collapse
Affiliation(s)
- Yoshihide Asano
- Department of Dermatology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masatoshi Jinnin
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Yasushi Kawaguchi
- Institute of Rheumatology, Tokyo Woman's Medical University, Tokyo, Japan
| | - Masataka Kuwana
- Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, Tokyo, Japan
| | - Daisuke Goto
- Department of Rheumatology, Faculty of Medicine, Univertity of Tsukuba, Ibaraki, Japan
| | - Shinichi Sato
- Department of Dermatology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Takehara
- Department of Molecular Pathology of Skin, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Ishikawa, Japan
| | - Masaru Hatano
- Graduate School of Medicine Department of Therapeutic Strategy for Heart Failure, The University of Tokyo, Tokyo, Japan
| | - Manabu Fujimoto
- Department of Dermatology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Naoki Mugii
- Section of Rehabilitation, Kanazawa University Hospital, Ishikawa, Japan
| | - Hironobu Ihn
- Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| |
Collapse
|
|
32
|
Nair V, Vasdev V, Kumar A, Shankar S, Nair V, Sharma A. Stem cell transplant in systemic sclerosis: An Indian experience. Int J Rheum Dis 2018; 21:859-865. [DOI: 10.1111/1756-185x.13262] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- Velu Nair
- Internal Medicine & Haematology; Armed Forces Medical College; Pune India
| | - Vivek Vasdev
- Rheumatology & Clinical Immunology; Army Hospital R & R; New Delhi India
| | - Abhishek Kumar
- Rheumatology & Clinical Immunology; Army Hospital R & R; New Delhi India
| | | | - Vivek Nair
- Dermatology; Maulana Azad Medical College; New Delhi India
| | - Ajay Sharma
- Rheumatology & Clinical Immunology; Army Hospital R & R; New Delhi India
| |
Collapse
|
|
33
|
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.
Collapse
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
| | | |
Collapse
|
|
34
|
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.
Collapse
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
| |
Collapse
|
|
35
|
Suzuki A, Kondoh Y, Fischer A. Recent advances in connective tissue disease related interstitial lung disease. Expert Rev Respir Med 2017; 11:591-603. [PMID: 28544856 DOI: 10.1080/17476348.2017.1335600] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
INTRODUCTION Interstitial lung disease (ILD) is a common manifestation of connective tissue disease (CTD). Although the majority of patients with CTD-ILD are stable or slowly progressive, a significant group exhibits a more severe and progressive decline. Interstitial pneumonia with autoimmune features (IPAF) describes the subset of patients with interstitial pneumonia who have features suggesting underlying autoimmunity, but whose features fall short of a clear diagnosis of CTD. Areas covered: In this focused review, we discuss recent advances in early detection, prognostic evaluation, and management of autoimmune forms of ILD. Expert commentary: Early detection of ILD and a better understanding of factors that impact prognostication may be helpful when making decisions regarding therapeutic interventions. The treatment of CTD-ILD should be comprehensive, is often fraught with challenges and can be complicated by comorbid conditions and extra-thoracic disease activities. Several large randomized studies have examined the impact of immunosuppressive therapy for CTD-ILD, however, additional studies are needed to determine the optimal treatment strategies. Future studies may provide additional information about the best treatments in patients with IPAF.
Collapse
Affiliation(s)
- Atsushi Suzuki
- a Department of Respiratory Medicine and Allergy , Tosei General Hospital , Seto , Japan
| | - Yasuhiro Kondoh
- a Department of Respiratory Medicine and Allergy , Tosei General Hospital , Seto , Japan
| | - Aryeh Fischer
- b Department of Medicine, Divisions of Rheumatology, Pulmonary Sciences and Critical Care Medicine , University of Colorado , Aurora , CO , USA
| |
Collapse
|
|
36
|
Zeher M, Papp G, Nakken B, Szodoray P. Hematopoietic stem cell transplantation in autoimmune disorders: From immune-regulatory processes to clinical implications. Autoimmun Rev 2017; 16:817-825. [PMID: 28572052 DOI: 10.1016/j.autrev.2017.05.020] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 04/28/2017] [Indexed: 12/29/2022]
Abstract
Autoimmune diseases are characterized by the development of autoreactive T- and B-cells targeting self-antigens, which eventually can result in chronic and persistent organ damage. The autologous hematopoietic stem cell transplantation (AHSCT) opened new avenues in the treatment of patients with severe, treatment-resistant autoimmune diseases. This paper reviews the immune-regulatory mechanisms behind AHSCT, and also summarizes the experiences of clinical practice related to the therapy in organ-specific and systemic autoimmune diseases. It seems that the intricate interplay of various immune competent cells with regulatory capacity control in a synergistic manner the repopulated immune system after AHSCT, which potentially leads to a significant clinical improvement in certain autoimmune diseases. However, the widespread use of AHSCT was intrinsically limited, due to the serious side-effects of conditioning treatment and relatively high treatment-related mortality; moreover, the development of new effective and safe therapeutic approaches and the dawn of biological agents further limited its indications in the last decade. Nevertheless, with an appropriate patient selection and increased experience of transplant centres, the risks can be minimized, and AHSCT remained still a reasonable choice in multiple sclerosis and systemic sclerosis when the conventional therapy failed and further progression of disease is inevitable.
Collapse
Affiliation(s)
- Margit Zeher
- Division of Clinical Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
| | - Gábor Papp
- Division of Clinical Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Britt Nakken
- Centre for Immune Regulation, Department of Immunology, University of Oslo, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Peter Szodoray
- Centre for Immune Regulation, Department of Immunology, University of Oslo, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| |
Collapse
|
|
37
|
Mina-Osorio P. Stem Cell Therapy in the Treatment of Rheumatic Diseases and Application in the Treatment of Systemic Lupus Erythematosus. NEXT-GENERATION THERAPIES AND TECHNOLOGIES FOR IMMUNE-MEDIATED INFLAMMATORY DISEASES 2017. [PMCID: PMC7123283 DOI: 10.1007/978-3-319-42252-7_9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Current systemic therapies help to improve the symptoms and quality of life for patients with severe life-threatening rheumatic diseases but provide no curative treatment. For the past two decades, preclinical and clinical studies of stem cell transplantation (SCT) have demonstrated tremendous therapeutic potential for patients with autoimmune rheumatic diseases. Herein, the current advances on stem cell therapies, both in animal models and clinical studies, are discussed, with particular attention on systemic lupus erythematosus (SLE). Despite extensive research and promising data, our knowledge on mechanisms of action for SCT, its administration route and timing, the optimal dose of cells, the cells’ fate and distribution in vivo, and the safety and efficacy of the treatments remains limited. Further research on stem cell biology is required to ensure that therapeutic safety and efficacy, as observed in animal models, can be successfully translated in clinical trials. Current understanding, limitations, and future directions for SCT with respect to rheumatic diseases are also discussed.
Collapse
|
|
38
|
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.
Collapse
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
| |
Collapse
|
|
39
|
van Rhijn-Brouwer FCC, Gremmels H, Fledderus JO, Radstake TRD, Verhaar MC, van Laar JM. Cellular Therapies in Systemic Sclerosis: Recent Progress. Curr Rheumatol Rep 2016; 18:12. [PMID: 26943351 PMCID: PMC4779139 DOI: 10.1007/s11926-015-0555-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease with a high mortality and morbidity. While progress has been made in terms of identifying high-risk patients and implementing new treatment strategies, therapeutic options remain limited. In the past few decades, various cellular therapies have emerged, which have been studied in SSc and other conditions. Here, we provide a comprehensive review of currently available cellular therapies and critically assess their merit as disease-modifying treatment for SSc. Currently, hematopoietic stem cell transplantation is the only cellular therapy that has demonstrated clinical effects on the immune system, neoangiogenesis, and fibrosis. Robust mechanistic studies as well as clinical trials are essential to move the field forward.
Collapse
Affiliation(s)
- Femke C C van Rhijn-Brouwer
- Department of Nephrology and Hypertension, Division of Internal Medicine and Dermatology, University Medical Center Utrecht, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands
| | - Hendrik Gremmels
- Department of Nephrology and Hypertension, Division of Internal Medicine and Dermatology, University Medical Center Utrecht, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands
| | - Joost O Fledderus
- Department of Nephrology and Hypertension, Division of Internal Medicine and Dermatology, University Medical Center Utrecht, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands
| | - Timothy R D Radstake
- Department of Rheumatology & Clinical Immunology, Division of Internal Medicine and Dermatology, University Medical Center Utrecht, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands
| | - Marianne C Verhaar
- Department of Nephrology and Hypertension, Division of Internal Medicine and Dermatology, University Medical Center Utrecht, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands
| | - Jacob M van Laar
- Department of Rheumatology & Clinical Immunology, Division of Internal Medicine and Dermatology, University Medical Center Utrecht, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands.
| |
Collapse
|
|
40
|
[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.
Collapse
|
|
41
|
Kelsey PJ, Oliveira MC, Badoglio M, Sharrack B, Farge D, Snowden JA. Haematopoietic stem cell transplantation in autoimmune diseases: From basic science to clinical practice. Curr Res Transl Med 2016; 64:71-82. [PMID: 27316390 DOI: 10.1016/j.retram.2016.03.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 03/31/2016] [Indexed: 12/20/2022]
Abstract
Based on animal studies and serendipitous clinical cases, haematopoietic stem cell transplantation (HSCT) has been used since 1995 as a specific treatment for patients with severe treatment-resistant autoimmune disease (ADs). Despite other clinical developments for autoimmune diseases, including biological therapies, there has been an ongoing requirement for HSCT in some diseases and several thousand procedures have been registered in databases for a wide variety of diseases, predominantly for treatment with autologous HSCT. Currently, the main indications are multiple sclerosis, systemic sclerosis and Crohn's disease, which are supported by large series and randomised controlled trials (RCTs), whereas retrospective registry analyses support benefit in a range of rarer indications. Research into mechanisms of action has provided insight into how tolerance may be achieved with an intensive one-off treatment. In addition to the profound anti-inflammatory and immunosuppressive effects provided by the cytotoxic regimen, long-term responses in some diseases may be explained by 'resetting' the immune system through thymic reprocessing and generation of increased T-regulatory cell activity. This review aims to summarise the gradual evolution of HSCT in severe autoimmune diseases over the last 20 years, focussing on the recent publication of clinical and scientific studies, as well as evidence-based guidelines and recommendations.
Collapse
Affiliation(s)
- P J Kelsey
- Departments of Haematology and Neurology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Glossop Road, Sheffield, UK.
| | - M-C Oliveira
- Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | | | - B Sharrack
- Departments of Haematology and Neurology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Glossop Road, Sheffield, UK
| | - D Farge
- St. Louis hospital, Internal Medicine and Vascular Diseases Unit, Paris, France; INSERM 1160 Unit, Paris 7 Diderot University, Sorbonne Paris Cite 1, Paris, France
| | - J A Snowden
- Departments of Haematology and Neurology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Glossop Road, Sheffield, UK
| |
Collapse
|
|
42
|
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]
|
|
43
|
Ramaswamy S, Jain S, Ravindran V. Hematopoietic stem cell transplantation for auto immune rheumatic diseases. World J Transplant 2016; 6:199-205. [PMID: 27011918 PMCID: PMC4801796 DOI: 10.5500/wjt.v6.i1.199] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Revised: 11/04/2015] [Accepted: 12/18/2015] [Indexed: 02/05/2023] Open
Abstract
Stem cells have their origins in the embryo and during the process of organogenesis, these differentiate into specialized cells which mature to form tissues. In addition, stem cell are characterized by an ability to indefinitely self renew. Stem cells are broadly classified into embryonic stem cells and adult stem cells. Adult stem cells can be genetically reprogrammed to form pluripotent stem cells and exist in an embroyonic like state. In the early phase of embryogenesis, human embryonic stem cells only exist transiently. Adult stem cells are omnipresent in the body and function to regenerate during the process of apoptosis or tissue repair. Hematopoietic stem cells (HSC) are adult stem cells that form blood and immune cells. Autoimmune responses are sustained due to the perennial persistence of tissue self autoantigens and/or auto reactive lymphocytes. Immune reset is a process leading to generation of fresh self-tolerant lymphocytes after chemotherapy induced elimination of self or autoreactive lymphocytes. This forms the basis for autologous HSC transplantation (HSCT). In the beginning HSCT had been limited to refractory autoimmune rheumatic diseases (AIRD) due to concern about transplant related mortality and morbidity. However HSCT for AIRD has come a long way with better understanding of patient selection, conditioning regime and supportive care. In this narrative review we have examined the available literature regarding the HSCT use in AIRD.
Collapse
|
|
44
|
Yasuoka H. Recent Treatments of Interstitial Lung Disease with Systemic Sclerosis. CLINICAL MEDICINE INSIGHTS-CIRCULATORY RESPIRATORY AND PULMONARY MEDICINE 2016; 9:97-110. [PMID: 26819563 PMCID: PMC4720185 DOI: 10.4137/ccrpm.s23315] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 09/15/2015] [Accepted: 09/23/2015] [Indexed: 02/06/2023]
Abstract
Systemic sclerosis (SSc) is a disorder characterized by immune dysfunction, microvascular injury, and fibrosis. Organ involvement in patients with SSc is variable; however, pulmonary involvement occurs in up to 90% of patients with SSc. Interstitial lung disease (ILD) is a major cause of mortality and, thus, a major determinant in the prognosis of patients with SSc. This review summarizes current findings about the characteristics of ILD in patients with SSc, selection of patients with SSc-ILD who are candidates for the treatment, and current treatment options.
Collapse
Affiliation(s)
- Hidekata Yasuoka
- Assistant Professor, Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Shinjuku, Tokyo, Japan
| |
Collapse
|
|
45
|
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.
Collapse
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
| | | |
Collapse
|
|
46
|
Mendoza FA, Mansoor M, Jimenez SA. Treatment of Rapidly Progressive Systemic Sclerosis: Current and Futures Perspectives. Expert Opin Orphan Drugs 2015; 4:31-47. [PMID: 27812432 PMCID: PMC5087809 DOI: 10.1517/21678707.2016.1114454] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Systemic Sclerosis (SSc) is a systemic autoimmune disease characterized by severe and often progressive cutaneous, pulmonary, cardiac and gastrointestinal tract fibrosis, cellular and humoral immunologic alterations, and pronounced fibroproliferative vasculopathy. There is no effective SSc disease modifying therapy. Patients with rapidly progressive SSc have poor prognosis with frequent disability and very high mortality. AREAS COVERED This paper reviews currently available therapeutic approaches for rapidly progressive SSc and discuss novel drugs under study for SSc disease modification. EXPERT OPINION The extent, severity, and rate of progression of SSc skin and internal organ involvement determines the optimal therapeutic interventions for SSc. Cyclophosphamide for progressive SSc-associated interstitial lung disease and mycophenolate for rapidly progressive cutaneous involvement have shown effectiveness. Methotrexate has been used for less severe skin progression and for patients unable to tolerate mycophenolate. Rituximab was shown to induce improvement in SSc-cutaneous and lung involvement. Autologous bone marrow transplantation is reserved for selected cases in whom poor survival risk outweighs the high mortality rate of the procedure. Novel agents capable of modulating fibrotic and inflammatory pathways involved in SSc pathogenesis, including tocilizumab, pirfenidone, tyrosine kinase inhibitors, lipid lysophosphatidic acid 1, and NOX4 inhibitors are currently under development for the treatment of rapidly progressive SSc.
Collapse
Affiliation(s)
- Fabian A. Mendoza
- Department of Medicine, Division of Rheumatology, Thomas Jefferson University Philadelphia, PA 19107, USA
- Jefferson Institute of Molecular Medicine, and Scleroderma Center, Thomas Jefferson University Philadelphia, PA 19107, USA
| | - Maryah Mansoor
- Department of Medicine, Division of Rheumatology, Thomas Jefferson University Philadelphia, PA 19107, USA
| | - Sergio A. Jimenez
- Jefferson Institute of Molecular Medicine, and Scleroderma Center, Thomas Jefferson University Philadelphia, PA 19107, USA
| |
Collapse
|
|
47
|
Volkmann ER, Furst DE. Management of Systemic Sclerosis-Related Skin Disease: A Review of Existing and Experimental Therapeutic Approaches. Rheum Dis Clin North Am 2015. [PMID: 26210126 DOI: 10.1016/j.rdc.2015.04.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The skin is the most common organ system involved in patients with systemic sclerosis (SSc). Nearly all patients experience cutaneous symptoms, including sclerosis, Raynaud's phenomenon, digital ulcers, telangiectasias, and calcinosis. In addition to posing functional challenges, cutaneous symptoms are often a major cause of pain, psychological distress, and body image dissatisfaction. The present article reviews the main features of SSc-related cutaneous manifestations and highlights an evidence-based treatment approach for treating each manifestation. This article also describes novel treatment approaches and opportunities for further research in managing this important clinical dimension of SSc.
Collapse
Affiliation(s)
- Elizabeth R Volkmann
- Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, 1000 Veteran Avenue, Suite 32-59, Los Angeles, CA 90095, USA.
| | - Daniel E Furst
- Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, 1000 Veteran Avenue, Suite 32-59, Los Angeles, CA 90095, USA
| |
Collapse
|
|
48
|
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.
Collapse
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
| |
Collapse
|
|
49
|
Nair V, Sharma A, Sharma S, Das S, Bhakuni DS, Narayanan K, Nair V, Shankar S. Successful autologous hematopoietic stem cell transplantation for a patient with rapidly progressive localized scleroderma. Int J Rheum Dis 2015; 18:366-71. [PMID: 25923607 DOI: 10.1111/1756-185x.12555] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Autologous hematopoietic stem cell transplant (HSCT) for rapidly progressive disease has not been reported in localized scleroderma. Our patient, a 16-year-old girl had an aggressive variant of localized scleroderma, mixed subtype (linear-generalized) with Parry Romberg syndrome, with no internal organ involvement, that was unresponsive to immunosuppressive therapy and was causing rapid disfigurement. She was administered autologous HSCT in June 2011 and has maintained drug-free remission with excellent functional status at almost 3.5 years of follow-up.
Collapse
Affiliation(s)
- Velu Nair
- Armed Forces Medical College, Pune, India
| | | | | | | | | | | | | | | |
Collapse
|
|
50
|
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.
Collapse
|