Cutaneous Chronic GVHD: Sclerodermatous and Morpheic Variants

  • Teresa S. HyunEmail author
  • Howard M. Shulman


Patients with cutaneous chronic GVHD (cGVHD) often undergo a progression to a sclerodermatous phase. This occurs in three pathways following a generalized lichenoid inflammatory state, less commonly out of a morpheic state or as eosinophilic fasciitis. The changes include fibrous remodeling of the dermal collagen, which eventually leads to dense dermal fibrosis and fibrosis within the underlying subcutaneous fat, resulting in contractures and frozen joints. The evolution from an inflammatory to sclerotic phase is a continuum. The pandermal sclerosis may be modified by immunosuppression, and there is variability from different sites. Evaluation of sclerodermatous chronic GVHD requires a full-thickness biopsy. However, because it is difficult to distinguish static from active changes, the diagnosis often relies on clinical evaluation. A framework for evaluating fibrosis after clinical intervention is proposed. Sclerodermatous cGVHD phenotypically resembles progressive systemic sclerosis (PSS). Pathobiological studies of the microvasculature’s role in the genesis of sclerosis indicate normal dermal capillary architecture and endothelial phenotype in cGVHD in contrast to PSS. Studies regarding a reduction of dermal vessels in patients with cGVHD are discordant. The current thinking is that the sclerosis evolves from a combination of cytokines and B-cell hyper-reactivity, leading to prolonged stimulation of fibrosis.


Sclerodermatous chronic GVHD Morpheic chronic GVHD Progressive systemic sclerosis Dermal microvascular changes in skin chronic GVHD Grading of skin sclerosis in chronic GVHD 


  1. 1.
    Inamoto Y, Storer BE, Petersdorf EW, et al. Incidence, risk factors, and outcomes of sclerosis in patients with chronic graft-versus-host disease. Blood. 2013;121(25):5098–103.CrossRefGoogle Scholar
  2. 2.
    Signori A, Crocchiolo R, Oneto R, et al. Chronic GVHD is associated with lower relapse risk irrespective of stem cell source among patients receiving transplantation from unrelated donors. Bone Marrow Transplant. 2012;47(11):1474–8.CrossRefGoogle Scholar
  3. 3.
    Filipovich AH, Weisdorf D, Pavletic S, et al. 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. 2005;11(12):945–56.CrossRefGoogle Scholar
  4. 4.
    Bilic E, Delimar V, Desnica L, et al. High prevalence of small- and large-fiber neuropathy in a prospective cohort of patients with moderate to severe chronic GvHD. Bone Marrow Transplant. 2016;51(11):1513–7.CrossRefGoogle Scholar
  5. 5.
    Gathings RM, Reddy R, Santa Cruz D, Brodell RT. Gadolinium-associated plaques: a new, distinctive clinical entity. JAMA Dermatol. 2015;151(3):316–9.CrossRefGoogle Scholar
  6. 6.
    Fleming JN, Nash RA, McLeod DO, et al. Capillary regeneration in scleroderma: stem cell therapy reverses phenotype? PLoS One. 2008;3(1):e1452.CrossRefGoogle Scholar
  7. 7.
    Aschwanden M, Halter JP, Walker UA, et al. Nail fold capillaroscopy differs widely between systemic sclerosis and chronic graft vs host disease of the skin. Rheumatology (Oxford). 2011;50(6):1168–9.CrossRefGoogle Scholar
  8. 8.
    Hofstee HM, de Waal TT, Zweegman S, et al. Nailfold capillary abnormalities in sclerodermatous chronic GVHD. Bone Marrow Transplant. 2013;48(12):1574–7.CrossRefGoogle Scholar
  9. 9.
    Biedermann BC, Sahner S, Gregor M, et al. Endothelial injury mediated by cytotoxic T lymphocytes and loss of microvessels in chronic graft versus host disease. Lancet. 2002;359(9323):2078–83.CrossRefGoogle Scholar
  10. 10.
    Fleming JN, Shulman HM, Nash RA, et al. Cutaneous chronic graft-versus-host disease does not have the abnormal endothelial phenotype or vascular rarefaction characteristic of systemic sclerosis. PLoS One. 2009;4(7):e6203.CrossRefGoogle Scholar
  11. 11.
    Zeiser R, Blazar BR. Pathophysiology of chronic graft-versus-host disease and therapeutic targets. N Engl J Med. 2017;377(26):2565–79.CrossRefGoogle Scholar
  12. 12.
    Alexander KA, Flynn R, Lineburg KE, et al. CSF-1-dependant donor-derived macrophages mediate chronic graft-versus-host disease. J Clin Invest. 2014;124(10):4266–80.CrossRefGoogle Scholar
  13. 13.
    Yamakawa T, Ohigashi H, Hashimoto D, et al. Vitamin A-coupled liposomes containing siRNA against HSP47 ameliorate skin fibrosis in chronic graft-versus-host disease. Blood. 2018;131(13):1476–85.CrossRefGoogle Scholar
  14. 14.
    Wang KS, Kim HT, Nikiforow S, et al. Antibodies targeting surface membrane antigens in patients with chronic graft-versus-host disease. Blood. 2017;130(26):2889–99.CrossRefGoogle Scholar
  15. 15.
    Inamoto Y, Martin PJ, Flowers ME, et al. Genetic risk factors for sclerotic graft-versus-host disease. Blood. 2016;128(11):1516–24.CrossRefGoogle Scholar
  16. 16.
    Sato Y, Murase K, Kato J, et al. Resolution of liver cirrhosis using vitamin A-coupled liposomes to deliver siRNA against a collagen-specific chaperone. Nat Biotechnol. 2008;26(4):431–42.CrossRefGoogle Scholar
  17. 17.
    Socie G. Treating chronic GVHD-induced fibrosis? Blood. 2018;131(13):1396–7.CrossRefGoogle Scholar
  18. 18.
    MacDonald KPA, Betts BC, Couriel D. Emerging therapeutics for the control of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2018;24(1):19–26.CrossRefGoogle Scholar
  19. 19.
    Du J, Paz K, Flynn R, et al. Pirfenidone ameliorates murine chronic GVHD through inhibition of macrophage infiltration and TGF-beta production. Blood. 2017;129(18):2570–80.CrossRefGoogle Scholar
  20. 20.
    Carpenter PA. How I conduct a comprehensive chronic graft-versus-host disease assessment. Blood. 2011;118(10):2679–87.CrossRefGoogle Scholar
  21. 21.
    Verrecchia F, Laboureau J, Verola O, et al. Skin involvement in scleroderma – where histological and clinical scores meet. Rheumatology (Oxford). 2007;46(5):833–41.CrossRefGoogle Scholar
  22. 22.
    Nash RA, McSweeney PA, Crofford LJ, 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(4):1388–96.CrossRefGoogle Scholar
  23. 23.
    Shulman HM, Cardona DM, Greenson JK, Hingorani S, Horn T, Huber E, Kreft A, Longerich T, Morton T, Myerson D, Prieto VG, Rosenberg A, Treister N, Washington K, Ziemer M, Pavletic SZ, Lee SJ, Flowers MED, Schultz KR, Jagasia M, Martin PJ, Vogelsang GB, Kleiner DE. NIH consensus development project on criteria for clinical trials in chronic graft-versus-host disease: II. The 2014 pathology working group report. Biol Blood Marrow Transplant. 2015;21(4):589–603.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Clinical Research DivisionFred Hutchinson Cancer Research CenterSeattleUSA
  2. 2.Department of PathologyUniversity of Washington School of MedicineSeattleUSA
  3. 3.Pathology Section, Seattle Cancer Care AllianceSeattleUSA

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