Export file:


  • RIS(for EndNote,Reference Manager,ProCite)
  • BibTex
  • Text


  • Citation Only
  • Citation and Abstract

Sclerodermatous GVHD after Allogeneic Bone Marrow Transplant: a Review

Nassau University Medical Center, East Meadow, NY 11554, USA

Chronic graft versus host disease (cGVHD) is the leading cause of non-relapse mortality after allogeneic hematopoietic bone marrow transplantation (HCT) for blood malignancy in patients who survive for more than two years. cGVHD can significantly affect quality of life and cause decreased mobility amongst other grave consequences such as end-organ damage, contributing to morbidity and mortality rates for recipients of HCT. Unlike acute GVHD (aGVHD), the chronic variant of graft versus host disease (GVHD) has complex immunopathology involving both humoral and cell immunity. It typically affects the integumentary system, though is known to also affect myofascial, mucocutaneous tissues as well as cause end organ damage ultimately resulting in death. Sclerodermatous cGVHD is a type of cGVHD characterized by involvement of the skin, subcutaneous tissue and fascia without evidence of disease in the viscera. Manifestations of this disease are often evocative of autoimmune disease, which is a self-directed inflammatory reaction to the innate and adaptive immune system in various tissues or multiple organ systems. This inflammatory reaction gives rise to autoantibodies as well as B-cell and T-cell mediated direct toxicity which can cause chronic inflammatory changes of tissues ultimately resulting in tissue scarring and end organ dysfunction. We aim to review the literature on this grave disease and elucidate aspects of the immunopathology of chronic sclerodermatous GVHD in hopes that it may lead to revelations inspiring novel therapies after its diagnosis or preventative measures before stem cell transplantation for malignancy.
  Article Metrics


1. Cooke KR, Luznik L, Sarantopoulos S, et al. (2016) The Biology of Chronic Graft-versus-Host Disease: A Task Force Report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease. Biol Blood Marrow Transplant 23: 211-234.

2. Jacobsohn DA, Kurland BF, Pidala J, et al. (2012) Correlation between NIH composite skin score, patient-reported skin score, and outcome: results from the Chronic GVHD Consortium. Blood 120: 2545-2552.    

3. Flowers ME, Inamoto Y, Carpenter PA, et al. (2011) Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. Blood 117: 3214-3219.    

4. Salhotra A, Tsai N, Thomas SH, et al. (2015). Sclerodermatous chronic GVHD in patients receiving tyrosine kinase inhibitors after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 50: 139-141.

5. Tyndall A, Dazzi F (2008) Chronic GVHD as an autoimmune disease. Best Pract Res Clin Haematol 21: 281-289.

6. McCormick LL, Zhang Y, Tootell E, et al. (1999) Anti-TGF-β Treatment Prevents Skin and Lung Fibrosis in Murine Sclerodermatous Graft-Versus-Host Disease: A Model for Human Scleroderma. J Immunol 163: 5693-5699.

7. Shulman HM, Kleiner D, Lee SJ, et al. (2006) Histopathologic diagnosis of chronic graft-versus-host disease: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: II. Pathology working group report. Biol Blood Marrow Transplant 12: 31-47.

8. Olivieri J, Coluzzi S, Attolico I, et al. (2011) Tirosine Kinase Inhibitors in Chronic Graft versus Host Disease: From Bench to Bedside. Sci World J 11: 1908-1931.    

9. Osmola-Mańkowska A, Silny W (2013) Assessment of chronic sclerodermoid Graft-versus-Host Disease patients, using 20MHz high-frequency ultrasonography flowersand cutometer methods. Skin Res Technol 19: e417-e422.    

10. Lang KS, Recher M (2005) Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease. Nature Med 11: 138-145.    

11. Brüggen M, Klein I, Greinix H, et al. (2014) Diverse T-cell responses characterize the different manifestations of cutaneous graft-versus-host disease. Blood 123: 290-299.    

12. Hofmeister CC, Quinn A, Cooke KR, et al. (2004) Graft-versus-host disease of the skin: life and death on the epidermal edge. Biol Blood Marrow Transplant 10: 366-372.    

13. Nikolic B, Lee S, Bronson RT, et al. (2000) Th1 and Th2 mediate acute graft-versus-host disease, each with distinct end-organ targets. J Clin Invest 105: 1289.    

14. Dander E, Balduzzi A, Zappa G, et al. (2009) Interleukin-17-producing T-helper cells as new potential player mediating graft-versus-host disease in patients undergoing allogeneic stem-cell transplantation. Transplantation 88: 1261-1272.    

15. Steinman L (2007) A brief history of TH17, the first major revision in the TH1/TH2 hypothesis of T cell-mediated tissue damage. Nat Med 13: 139-145.    

16. Broady R, Yu J, Chow V, et al. (2010) Cutaneous GVHD is associated with the expansion of tissue-localized Th1 and not Th17 cells. Blood 116: 5748-5751.    

17. Annacker O, Burlen-Defranoux O, Pimenta-Araujo R, et al. (2000) Regulatory CD4 T Cells Control the Size of the Peripheral Activated/Memory CD4 T Cell Compartment. Immunol 164: 3573-3580.    

18. Shimabukuro-Vornhagen A, Hallek MJ, Storb RF, et al. (2009). The role of B cells in the pathogenesis of graft-versus-host disease. Blood 114: 4919-4927.    

19. Robson NC, Donachie AM, Mowat AM (2008) Simultaneous presentation and cross-presentation of immune-stimulating complex-associated cognate antigen by antigen-specific B cells. Eur J Immunol 38: 1238-1246.    

20. Filipovich AH, Weisdorf D, Pavletic S, et al. (2005) National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 11: 945-956.    

21. Lee SJ (2010) Have we made progress in the management of chronic graft-vs-host disease? Best Pract Res 23: 529-535.    

22. Choi SW, Levine JE, Ferrara JLM (2010) Pathogenesis and Management of Graft versus Host Disease. Immunol Allergy Clin North Am 30: 75-101.    

23. de Masson A, Bouaziz J, de Latour RP, et al. (2012) Limited efficacy and tolerance of imatinib mesylate in steroid-refractory sclerodermatous chronic GVHD. Blood 120: 5089-5090.    

24. Denton CP, Merkel PA, Furst DE, et al. (2007) Recombinant human anti-transforming growth factor beta1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192. Arthritis Rheum 56: 323-333.    

25. Schlaak M, Schwind S, Wetzig T, et al. (2010) UVA (UVA-1) therapy for the treatment of acute GVHD of the skin. Bone Marrow Transplant 45: 1741-1748.    

26. Sanchez-Ortega I, Servitje O, Arnan M, et al. (2012) Dasatinib as salvage therapy for steroid refractory and imatinib resistant or intolerant sclerotic chronic graft-versus-host disease. Biol Blood Marrow Transplant 182: 318-323.

27. Ratanatharathorn V, Carson E, Reynolds C, et al. (2000) Anti-CD20 chimeric monoclonal antibody treatment of refractory immune-mediated thrombocytopenia in a patient with chronic graft-versus-host disease. Ann Intern Med 133: 275-279.

28. Kim SJ, Lee JW, Jung CW, et al. (2010) Weekly rituximab followed by monthly rituximab treatment for steroid-refractory chronic graft-versus-host disease: results from a prospective, multicenter, phase II study. Haematologica 95: 1935-1942.    

29. Lee SJ, Flowers ME (2008) Recognizing and managing chronic graft-versus-host disease. Hematology Am Soc Hematol Educ Program 134-141.

30. Zhou H, Guo M, Bian C, et al. (2010) Efficacy of Bone Marrow-Derived Mesenchymal Stem Cells in the Treatment of Sclerodermatous Chronic Graft-versus-Host Disease: Clinical Report. Biol Blood Marrow Transplant 16: 403-412.    

31. Pène J, Chevalier S, Preisser L, et al. (2008) Chronically inflamed human tissues are infiltrated by highly differentiated Th17 lymphocytes. J Immunol 180: 7423.    

32. Drobyski WR, Pasquini M, Kovatovic K, et al. (2011) Tocilizumab for the Treatment of Steroid Refractory Graft-versus-Host Disease. Biol Blood Marrow Transplant 17: 1862-1868.    

33. Hori A, Kanda Y, Goyama S, et al. (2005) A prospective trial to evaluate the safety and efficacy of pravastatin for the treatment of refractory chronic graft-versus-host disease. Transplantation 79: 372-374.    

34. Distler JHW, Distler O (2010) Tyrosine kinase inhibitors for the treatment of fibrotic diseases such as systemic sclerosis: towards molecular targeted therapies. Ann Rheum Dis 69: i48-i51.    

Copyright Info: © 2017, Gagan Raju, et al., licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

Download full text in PDF

Export Citation

Article outline

Show full outline
Copyright © AIMS Press All Rights Reserved