pp 1–9 | Cite as

Hematopoietic Stem Cell Transplantation for Systemic Sclerosis: Review of Current Status

  • Alan TyndallEmail author
Review Article


Three prospective controlled clinical trials and numerous small series and case reports have confirmed that durable, drug-free remission in systemic sclerosis is possible via an autologous hematopoietic stem cell transplantation. Similar results have been seen in other autoimmune diseases. The exact mechanism by which this immune “reset” was achieved in some but not all cases remains elusive, but includes major reduction of autoreactive immune competent cells, re-establishment of T- and B cell regulatory networks and normalization of tissue niche function, particularly vascular. Some aspects regarding mobilization, conditioning and graft manipulation still remain open, but clearly a significant toxicity is associated with all effective regimens at present, and therefore patient selection remains a key issue. In the hematology/oncology arena, major efforts are being made to reduce genotoxic and other collateral toxicity induced by current mobilization and conditioning protocols, which may also translate to autoimmune disease. These include developments in rapid mobilization and antibody drug conjugate conditioning technology. If effective, such low-toxicity regimens might be applied to autoimmune disease at an earlier stage before chronicity of autoimmunity has been established, thus changing the therapeutic paradigm.


Compliance with Ethical Standards


There was no funding associated with the preparation of this review.

Conflict of interest

AT is a co-founder and shareholder of Magenta Therapeutics.


  1. 1.
    Marmont A, Tyndall A, Gratwohl A, Vischer T. Hemopoietic stem cell precursor-cell transplants for autoimmune diseases. Lancet. 1995;345:978.CrossRefGoogle Scholar
  2. 2.
    Fassas A, Anagnostopoulos A, Kazis A, Kapinas K, Sakellari I, Kimiskidis V, et al. Peripheral blood stem cell transplantation in the treatment of progressive multiple sclerosis: first results of a pilot study. Bone Marrow Transplant. 1997;20:631–8.CrossRefGoogle Scholar
  3. 3.
    Snowden JA, Biggs JC, Brooks PM. Autologous blood stem cell transplantation for autoimmune diseases. Lancet Lond Engl. 1996;348:1112–3.CrossRefGoogle Scholar
  4. 4.
    Sullivan KM, Furst DE. The evolving role of blood and marrow transplantation for the treatment of autoimmune diseases. J Rheumatol Suppl. 1997;48:1–4.Google Scholar
  5. 5.
    Tyndall A, Gratwohl A. Blood and marrow stem cell transplants in auto-immune disease: a consensus report written on behalf of the European League against Rheumatism (EULAR) and the European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 1997;19:643–5.CrossRefGoogle Scholar
  6. 6.
    Lowenthal RM, Cohen ML, Atkinson K, Biggs JC. Apparent cure of rheumatoid arthritis by bone marrow transplantation. J Rheumatol. 1993;20:137–40.Google Scholar
  7. 7.
    McKendry RJ, Huebsch L, Leclair B. Progression of rheumatoid arthritis following bone marrow transplantation. A case report with a 13-year followup. Arthritis Rheum. 1996;39:1246–53.CrossRefGoogle Scholar
  8. 8.
    Morton JI, Siegel BV. Transplantation of autoimmune potential. IV. Reversal of the NZB autoimmune syndrome by bone marrow transplantation. Transplantation. 1979;27:133–4.CrossRefGoogle Scholar
  9. 9.
    Knaan-Shanzer S, Houben P, Kinwel-Bohré EP, van Bekkum DW. Remission induction of adjuvant arthritis in rats by total body irradiation and autologous bone marrow transplantation. Bone Marrow Transplant. 1991;8:333–8.Google Scholar
  10. 10.
    Tamm M, Gratwohl A, Tichelli A, Perruchoud AP, Tyndall A. Autologous haemopoietic stem cell transplantation in a patient with severe pulmonary hypertension complicating connective tissue disease. Ann Rheum Dis. 1996;55:779–80.CrossRefGoogle Scholar
  11. 11.
    Marmont AM, van Lint MT, Gualandi F, Bacigalupo A. Autologous marrow stem cell transplantation for severe systemic lupus erythematosus of long duration. Lupus. 1997;6:545–8.CrossRefGoogle Scholar
  12. 12.
    Cooley HM, Snowden JA, Grigg AP, Wicks IP. Outcome of rheumatoid arthritis and psoriasis following autologous stem cell transplantation for hematologic malignancy. Arthritis Rheum. 1997;40:1712–5.CrossRefGoogle Scholar
  13. 13.
    van Laar JM, Farge D, Sont JK, Naraghi K, Marjanovic Z, Larghero J, et al. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA. 2014;311:2490–8.CrossRefGoogle Scholar
  14. 14.
    Sullivan KM, Goldmuntz EA, Keyes-Elstein L, McSweeney PA, Pinckney A, Welch B, et al. Myeloablative autologous stem-cell transplantation for severe scleroderma. N Engl J Med. 2018;378:35–47.CrossRefGoogle Scholar
  15. 15.
    Burt RK, Shah SJ, Dill K, Grant T, Gheorghiade M, Schroeder J, et al. Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial. Lancet Lond Engl. 2011;378:498–506.CrossRefGoogle Scholar
  16. 16.
    Burt RK, Balabanov R, Burman J, Sharrack B, Snowden JA, Oliveira MC, et al. Effect of nonmyeloablative hematopoietic stem cell transplantation vs continued disease-modifying therapy on disease progression in patients with relapsing-remitting multiple sclerosis: a randomized clinical trial. JAMA. 2019;321:165–74.CrossRefGoogle Scholar
  17. 17.
    Tyndall A. Hematopoietic stem cell transplantation for autoimmune diseases: more than just prolonged immunosuppression. Curr Opin Hematol. 2018;25:433–40.Google Scholar
  18. 18.
    Snowden JA, Badoglio M, Labopin M, Giebel S, McGrath E, Marjanovic Z, et al. Evolution, trends, outcomes, and economics of hematopoietic stem cell transplantation in severe autoimmune diseases. Blood Adv. 2017;1:2742–55.CrossRefGoogle Scholar
  19. 19.
    Muraro PA, Pasquini M, Atkins HL, Bowen JD, Farge D, Fassas A, et al. Long-term outcomes after autologous hematopoietic stem cell transplantation for multiple sclerosis. JAMA Neurol. 2017;74:459–69.CrossRefGoogle Scholar
  20. 20.
    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.CrossRefGoogle Scholar
  21. 21.
    Alten R, Mariette X, Lorenz H-M, Galeazzi M, Cantagrel A, Nüßlein HG, et al. Real-world predictors of 12-month intravenous abatacept retention in patients with rheumatoid arthritis in the ACTION observational study. RMD Open. 2017;3:e000538.CrossRefGoogle Scholar
  22. 22.
    Alten R, Mariette X, Lorenz H-M, Nüßlein H, Galeazzi M, Navarro F, et al. Predictors of abatacept retention over 2 years in patients with rheumatoid arthritis: results from the real-world ACTION study. Clin Rheumatol. 2019;38:1413–24.CrossRefGoogle Scholar
  23. 23.
    Ebina K, Hashimoto M, Yamamoto W, Ohnishi A, Kabata D, Hirano T, et al. Drug retention and discontinuation reasons between seven biologics in patients with rheumatoid arthritis—the ANSWER cohort study. PLoS One. 2018;13:e0194130.CrossRefGoogle Scholar
  24. 24.
    Jessop H, Farge D, Saccardi R, Alexander T, Rovira M, Sharrack B, et al. General information for patients and carers considering haematopoietic stem cell transplantation (HSCT) for severe autoimmune diseases (ADs): a position statement from the EBMT Autoimmune Diseases Working Party (ADWP), the EBMT Nurses Group, the EBMT Patient, Family and Donor Committee and the Joint Accreditation Committee of ISCT and EBMT (JACIE). Bone Marrow Transplant. 2019. Scholar
  25. 25.
    Gratwohl A, Passweg J, Bocelli-Tyndall C, Fassas A, van Laar JM, Farge D, et al. Autologous hematopoietic stem cell transplantation for autoimmune diseases. Bone Marrow Transplant. 2005;35:869–79.CrossRefGoogle Scholar
  26. 26.
    Muraro PA, Martin R, Mancardi GL, Nicholas R, Sormani MP, Saccardi R. Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis. Nat Rev Neurol. 2017;13:391–405.CrossRefGoogle Scholar
  27. 27.
    Burt RK, Oliveira MC, Shah SJ, Moraes DA, Simoes B, Gheorghiade M, et al. Cardiac involvement and treatment-related mortality after non-myeloablative haemopoietic stem-cell transplantation with unselected autologous peripheral blood for patients with systemic sclerosis: a retrospective analysis. Lancet Lond Engl. 2013;381:1116–24.CrossRefGoogle Scholar
  28. 28.
    Thomas ED. A history of haemopoietic cell transplantation. Br J Haematol. 1999;105:330–9.CrossRefGoogle Scholar
  29. 29.
    Farge D, Burt RK, Oliveira M-C, Mousseaux E, Rovira M, Marjanovic Z, et al. Cardiopulmonary assessment of patients with systemic sclerosis for hematopoietic stem cell transplantation: recommendations from the European Society for Blood and Marrow Transplantation Autoimmune Diseases Working Party and collaborating partners. Bone Marrow Transplant. 2017;52:1495–503.CrossRefGoogle Scholar
  30. 30.
    Snowden JA, Saccardi R, Allez M, Ardizzone S, Arnold R, Cervera R, et al. Haematopoietic SCT in severe autoimmune diseases: updated guidelines of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 2012;47:770–90.CrossRefGoogle Scholar
  31. 31.
    Bissell L-A, Dumitru RB, Erhayiem B, Abignano G, Fent G, Kidambi A, et al. Incidental significant arrhythmia in scleroderma associates with cardiac magnetic resonance measure of fibrosis and hs-TnI and NT-proBNP. Rheumatol Oxf Engl. 2019;58:1221–6.CrossRefGoogle Scholar
  32. 32.
    Tyndall AJ, Bannert B, Vonk M, Airò P, Cozzi F, Carreira PE, et al. Causes and risk factors for death in systemic sclerosis: a study from the EULAR scleroderma trials and research (EUSTAR) database. Ann Rheum Dis. 2010;69:1809–15.CrossRefGoogle Scholar
  33. 33.
    McNearney TA, Reveille JD, Fischbach M, Friedman AW, Lisse JR, Goel N, et al. Pulmonary involvement in systemic sclerosis: associations with genetic, serologic, sociodemographic, and behavioral factors. Arthritis Rheum. 2007;57:318–26.CrossRefGoogle Scholar
  34. 34.
    Roofeh D, Jaafar S, Vummidi D, Khanna D. Management of systemic sclerosis-associated interstitial lung disease. Curr Opin Rheumatol. 2019;31:241–9.CrossRefGoogle Scholar
  35. 35.
    Martini A, Maccario R, Ravelli A, Montagna D, De Benedetti F, Bonetti F, et al. Marked and sustained improvement 2 years after autologous stem cell transplantation in a girl with systemic sclerosis. Arthritis Rheum. 1999;42:807–11.CrossRefGoogle Scholar
  36. 36.
    Forbes A, Marie I. Gastrointestinal complications: the most frequent internal complications of systemic sclerosis. Rheumatol Oxf Engl. 2009;48(Suppl 3):36–9.Google Scholar
  37. 37.
    Roberts CGP, Hummers LK, Ravich WJ, Wigley FM, Hutchins GM. A case-control study of the pathology of oesophageal disease in systemic sclerosis (scleroderma). Gut. 2006;55:1697–703.CrossRefGoogle Scholar
  38. 38.
    Aschwanden M, Daikeler T, Jaeger KA, Thalhammer C, Gratwohl A, Matucci-Cerinic M, et al. Rapid improvement of nailfold capillaroscopy after intense immunosuppression for systemic sclerosis and mixed connective tissue disease. Ann Rheum Dis. 2008;67:1057–9.CrossRefGoogle Scholar
  39. 39.
    Miniati I, Guiducci S, Conforti ML, Rogai V, Fiori G, Cinelli M, et al. Autologous stem cell transplantation improves microcirculation in systemic sclerosis. Ann Rheum Dis. 2009;68:94–8.CrossRefGoogle Scholar
  40. 40.
    Fleming JN, Nash RA, McLeod DO, Fiorentino DF, Shulman HM, Connolly MK, et al. Capillary regeneration in scleroderma: stem cell therapy reverses phenotype? PLoS One. 2008;3:e1452.CrossRefGoogle Scholar
  41. 41.
    Bhattacharyya A, Sahhar J, Milliken S, Ma D, Englert H, Tymms K, et al. Autologous hematopoietic stem cell transplant for systemic sclerosis improves anemia from gastric antral vascular ectasia. J Rheumatol. 2015;42:554–5.CrossRefGoogle Scholar
  42. 42.
    Nash RA, McSweeney PA, Crofford LJ, Abidi M, Chen C-S, Godwin JD, et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the US multicenter pilot study. Blood. 2007;110:1388–96.CrossRefGoogle Scholar
  43. 43.
    van Bon L, Popa C, Huijbens R, Vonk M, York M, Simms R, et al. Distinct evolution of TLR-mediated dendritic cell cytokine secretion in patients with limited and diffuse cutaneous systemic sclerosis. Ann Rheum Dis. 2010;69:1539–47.CrossRefGoogle Scholar
  44. 44.
    Alexander T, Thiel A, Rosen O, Massenkeil G, Sattler A, Kohler S, et al. Depletion of autoreactive immunologic memory followed by autologous hematopoietic stem cell transplantation in patients with refractory SLE induces long-term remission through de novo generation of a juvenile and tolerant immune system. Blood. 2009;113:214–23.CrossRefGoogle Scholar
  45. 45.
    Muraro PA, Robins H, Malhotra S, Howell M, Phippard D, Desmarais C, et al. T cell repertoire following autologous stem cell transplantation for multiple sclerosis. J Clin Invest. 2014;124:1168–72.CrossRefGoogle Scholar
  46. 46.
    Delemarre EM, van den Broek T, Mijnheer G, Meerding J, Wehrens EJ, Olek S, et al. Autologous stem cell transplantation aids autoimmune patients by functional renewal and TCR diversification of regulatory T cells. Blood. 2016;127:91–101.CrossRefGoogle Scholar
  47. 47.
    Malmegrim KCR, Lima-Júnior JR, Arruda LCM, de Azevedo JTC, de Oliveira GLV, Oliveira MC. Autologous hematopoietic stem cell transplantation for autoimmune diseases: from mechanistic insights to biomarkers. Front Immunol. 2018;9:2602.CrossRefGoogle Scholar
  48. 48.
    Farge D, Arruda LCM, Brigant F, Clave E, Douay C, Marjanovic Z, et al. Long-term immune reconstitution and T cell repertoire analysis after autologous hematopoietic stem cell transplantation in systemic sclerosis patients. J Hematol OncolJ Hematol Oncol. 2017;10:21.CrossRefGoogle Scholar
  49. 49.
    Michel L, Farge D, Baraut J, Marjanovic Z, Jean-Louis F, Porcher R, et al. Evolution of serum cytokine profile after hematopoietic stem cell transplantation in systemic sclerosis patients. Bone Marrow Transplant. 2016;51:1146–9.CrossRefGoogle Scholar
  50. 50.
    Tsukamoto H, Nagafuji K, Horiuchi T, Mitoma H, Niiro H, Arinobu Y, et al. Analysis of immune reconstitution after autologous CD34+ stem/progenitor cell transplantation for systemic sclerosis: predominant reconstitution of Th1 CD4+ T cells. Rheumatol Oxf Engl. 2011;50:944–52.CrossRefGoogle Scholar
  51. 51.
    Taroni JN, Mahoney JM, Whitfield ML. The mechanistic implications of gene expression studies in SSc: insights from systems biology. Curr Treat Opt Rheumatol. 2017;3:181–92.CrossRefGoogle Scholar
  52. 52.
    Franks JM, Martyanov V, Cai G, Wang Y, Li Z, Wood TA, et al. A machine learning classifier for assigning individual patients with systemic sclerosis to intrinsic molecular subsets. Arthritis Rheumatol Hoboken NJ. 2019. Scholar
  53. 53.
    Rose NR. Prediction and prevention of autoimmune disease in the 21st century: a review and preview. Am J Epidemiol. 2016;183:403–6.CrossRefGoogle Scholar
  54. 54.
    Arbuckle MR, McClain MT, Rubertone MV, Scofield RH, Dennis GJ, James JA, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med. 2003;349:1526–33.CrossRefGoogle Scholar
  55. 55.
    Rubertone MV, Brundage JF. The defense medical surveillance system and the department of defense serum repository: glimpses of the future of public health surveillance. Am J Public Health. 2002;92:1900–4.CrossRefGoogle Scholar
  56. 56.
    Munroe ME, Lu R, Zhao YD, Fife DA, Robertson JM, Guthridge JM, et al. Altered type II interferon precedes autoantibody accrual and elevated type I interferon activity prior to systemic lupus erythematosus classification. Ann Rheum Dis. 2016;75:2014–21.CrossRefGoogle Scholar
  57. 57.
    Slight-Webb S, Lu R, Ritterhouse LL, Munroe ME, Maecker HT, Fathman CG, et al. Autoantibody-positive healthy individuals display unique immune profiles that may regulate autoimmunity. Arthritis Rheumatol Hoboken NJ. 2016;68:2492–502.CrossRefGoogle Scholar
  58. 58.
    Cope AP. Emerging therapies for pre-RA. Best Pract Res Clin Rheumatol. 2017;31:99–111.CrossRefGoogle Scholar
  59. 59.
    Minier T, Guiducci S, Bellando-Randone S, Bruni C, Lepri G, Czirják L, et al. Preliminary analysis of the very early diagnosis of systemic sclerosis (VEDOSS) EUSTAR multicentre study: evidence for puffy fingers as a pivotal sign for suspicion of systemic sclerosis. Ann Rheum Dis. 2014;73:2087–93.CrossRefGoogle Scholar
  60. 60.
    Bos WH, Dijkmans BC, Boers M, van de Stadt RJ, van Schaardenburg D. Effect of dexamethasone on autoantibody levels and arthritis development in patients with arthralgia: a randomised trial. Ann Rheum Dis. 2010;69:571–4.CrossRefGoogle Scholar
  61. 61.
    van den Hombergh WMT, Kersten BE, Knaapen-Hans HKA, Thurlings RM, van der Kraan PM, van den Hoogen FHJ, et al. Hit hard and early: analysing the effects of high-dose methylprednisolone on nailfold capillary changes and biomarkers in very early systemic sclerosis: study protocol for a 12-week randomised controlled trial. Trials. 2018;19:449.CrossRefGoogle Scholar
  62. 62.
    Gerlag DM, Safy M, Maijer KI, Tang MW, Tas SW, Starmans-Kool MJF, et al. Effects of B-cell directed therapy on the preclinical stage of rheumatoid arthritis: the PRAIRI study. Ann Rheum Dis. 2019;78:179–85.CrossRefGoogle Scholar
  63. 63.
    Tsuchikama K, An Z. Antibody-drug conjugates: recent advances in conjugation and linker chemistries. Protein Cell. 2018;9:33–46.CrossRefGoogle Scholar
  64. 64.
    Birrer MJ, Moore KN, Betella I, Bates RC. Antibody-drug conjugate-based therapeutics: state of the science. J Natl Cancer Inst. 2019;11:djz035.Google Scholar
  65. 65.
    Kowal-Bielecka O, Fransen J, Avouac J, Becker M, Kulak A, Allanore Y, et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis. 2017;76:1327–39.CrossRefGoogle Scholar
  66. 66.
    Sullivan KM, Majhail NS, Bredeson C, Carpenter PA, Chatterjee S, Crofford LJ, et al. Systemic sclerosis as an indication for autologous hematopoietic cell transplantation: position statement from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2018;24:1961–4.CrossRefGoogle Scholar
  67. 67.
    Fernández-Codina A, Walker KM, Pope JE, Scleroderma Algorithm Group. Treatment algorithms for systemic sclerosis according to experts. Arthritis Rheumatol Hoboken NJ. 2018;70:1820–8.CrossRefGoogle Scholar
  68. 68.
    Hawkey CJ, Allez M, Clark MM, et al. Autologous hematopoetic stem cell transplantation for refractory Crohn disease: a randomized clinical trial. JAMA. 2015;314(23):2524–34.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of RheumatologyUniversity of BaselBaselSwitzerland
  2. 2.BottmingenSwitzerland

Personalised recommendations