Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Understanding and treatment of cutaneous graft-versus-host-disease

Bone Marrow Transplantation volume 58, pages 1298–1313 (2023)Cite this article

Subjects

Abstract

The skin is the outermost mechanical barrier where dynamic immune reactions take place and is the most commonly affected site in both acute and chronic graft-versus-host disease (GVHD). If not properly treated, pain and pruritis resulting from cutaneous GVHD can increase the risk of secondary infection due to erosions, ulcerations, and damage of underlying tissues. Furthermore, resulting disfiguration can cause distress and significantly impact patients’ quality of life. Thus, a deeper understanding of skin-specific findings of GVHD is needed. This review will highlight some promising results of recent pre-clinical studies on the pathophysiology of skin GVHD and summarize the diagnostic and staging/grading procedures according to the clinical manifestations of skin GVHD. In addition, we will summarize outcomes of various GVHD treatments, including skin-specific response rates.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Pathophysiology of acute cutaneous graft vs host disease.
Fig. 2: Pathophysiology of chronic cutaneous grafts vs host disease.
Fig. 3: Typical clinical features of acute cutaneous graft-versus-host disease (GVHD).
Fig. 4: Stevens-Johnson Syndrome/toxic epidermal necrolysis-like presentation of acute cutaneous graft-versus-host disease.
Fig. 5: Chronic graft-versus-host disease presenting with lichen-planus like violaceous thin papules.
Fig. 6: Body surface area estimation for the staging of acute cutaneous graft-versus-host disease.
Fig. 7: Chronic graft-versus-host disease with deep sclerosis.
Fig. 8: Lichen sclerosus-like epidermal chronic graft-versus-host disease with mild erythema.

Similar content being viewed by others

References

  1. Penack O, Marchetti M, Ruutu T, Aljurf M, Bacigalupo A, Bonifazi F, et al. Prophylaxis and management of graft versus host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation. Lancet Haematol. 2020;7:e157–e67.

    Article  PubMed  Google Scholar 

  2. Shlomchik WD. Graft-versus-host disease. Nat Rev Immunol. 2007;7:340–52.

    Article  CAS  PubMed  Google Scholar 

  3. Bolanos-Meade J, Hamadani M, Wu J, Al Malki MM, Martens MJ, Runaas L, et al. Post-transplantation cyclophosphamide-based graft-versus-host disease prophylaxis. N Engl J Med. 2023;388:2338–48.

    Article  CAS  PubMed  Google Scholar 

  4. Flowers ME, Martin PJ. How we treat chronic graft-versus-host disease. Blood. 2015;125:606–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hillen U, Hausermann P, Massi D, Janin A, Wolff D, Lawitschka A, et al. Consensus on performing skin biopsies, laboratory workup, evaluation of tissue samples and reporting of the results in patients with suspected cutaneous graft-versus-host disease. J Eur Acad Dermatol Venereol. 2015;29:948–54.

    Article  CAS  PubMed  Google Scholar 

  6. Matzinger P. The danger model: a renewed sense of self. Science. 2002;296:301–5.

    Article  CAS  PubMed  Google Scholar 

  7. Santos ESP, Bennett CL, Chakraverty R. Unraveling the mechanisms of cutaneous graft-versus-host disease. Front Immunol. 2018;9:963.

    Article  Google Scholar 

  8. Gooptu M, Koreth J. Translational and clinical advances in acute graft-versus-host disease. Haematologica. 2020;105:2550–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zeiser R, Blazar BR. Acute graft-versus-host disease - biologic process, prevention, and therapy. N Engl J Med. 2017;377:2167–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zeiser R. Advances in understanding the pathogenesis of graft-versus-host disease. Br J Haematol. 2019;187:563–72.

    Article  PubMed  Google Scholar 

  11. Reddy P, Ferrara JL. Immunobiology of acute graft-versus-host disease. Blood Rev. 2003;17:187–94.

    Article  PubMed  Google Scholar 

  12. Choi J, Ziga ED, Ritchey J, Collins L, Prior JL, Cooper ML, et al. IFNgammaR signaling mediates alloreactive T-cell trafficking and GVHD. Blood. 2012;120:4093–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Nikolic B, Lee S, Bronson RT, Grusby MJ, Sykes M. Th1 and Th2 mediate acute graft-versus-host disease, each with distinct end-organ targets. J Clin Investig. 2000;105:1289–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Carlson MJ, West ML, Coghill JM, Panoskaltsis-Mortari A, Blazar BR, Serody JS. In vitro-differentiated TH17 cells mediate lethal acute graft-versus-host disease with severe cutaneous and pulmonary pathologic manifestations. Blood. 2009;113:1365–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zeiser R, Blazar BR. Pathophysiology of chronic graft-versus-host disease and therapeutic targets. N Engl J Med. 2017;377:2565–79.

    Article  CAS  PubMed  Google Scholar 

  16. Martires KJ, Baird K, Citrin DE, Hakim FT, Pavletic SZ, Cowen EW. Localization of sclerotic-type chronic graft-vs-host disease to sites of skin injury: potential insight into the mechanism of isomorphic and isotopic responses. Arch Dermatol. 2011;147:1081–6.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Flynn R, Paz K, Du J, Reichenbach DK, Taylor PA, Panoskaltsis-Mortari A, et al. Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism. Blood. 2016;127:2144–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zanin-Zhorov A, Weiss JM, Nyuydzefe MS, Chen W, Scher JU, Mo R, et al. Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism. Proc Natl Acad Sci USA. 2014;111:16814–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Edinger M, Hoffmann P, Ermann J, Drago K, Fathman CG, Strober S, et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med. 2003;9:1144–50.

    Article  CAS  PubMed  Google Scholar 

  20. Chen X, Vodanovic-Jankovic S, Johnson B, Keller M, Komorowski R, Drobyski WR. Absence of regulatory T-cell control of TH1 and TH17 cells is responsible for the autoimmune-mediated pathology in chronic graft-versus-host disease. Blood. 2007;110:3804–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zorn E, Kim HT, Lee SJ, Floyd BH, Litsa D, Arumugarajah S, et al. Reduced frequency of FOXP3+ CD4+CD25+ regulatory T cells in patients with chronic graft-versus-host disease. Blood. 2005;106:2903–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Caramalho I, Nunes-Cabaco H, Foxall RB, Sousa AE. Regulatory T-cell development in the human thymus. Front Immunol. 2015;6:395.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Hoffmann P, Edinger M. CD4+CD25+ regulatory T cells and graft-versus-host disease. Semin Hematol. 2006;43:62–9.

    Article  CAS  PubMed  Google Scholar 

  24. Flynn R, Du J, Veenstra RG, Reichenbach DK, Panoskaltsis-Mortari A, Taylor PA, et al. Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans. Blood. 2014;123:3988–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Jin H, Ni X, Deng R, Song Q, Young J, Cassady K, et al. Antibodies from donor B cells perpetuate cutaneous chronic graft-versus-host disease in mice. Blood. 2016;127:2249–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. MacDonald KP, Hill GR, Blazar BR. Chronic graft-versus-host disease: biological insights from preclinical and clinical studies. Blood. 2017;129:13–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Svegliati S, Olivieri A, Campelli N, Luchetti M, Poloni A, Trappolini S, et al. Stimulatory autoantibodies to PDGF receptor in patients with extensive chronic graft-versus-host disease. Blood. 2007;110:237–41.

    Article  CAS  PubMed  Google Scholar 

  28. Yamakawa T, Ohigashi H, Hashimoto D, Hayase E, Takahashi S, Miyazaki M, et al. Vitamin A-coupled liposomes containing siRNA against HSP47 ameliorate skin fibrosis in chronic graft-versus-host disease. Blood. 2018;131:1476–85.

    Article  CAS  PubMed  Google Scholar 

  29. Alexander KA, Flynn R, Lineburg KE, Kuns RD, Teal BE, Olver SD, et al. CSF-1-dependant donor-derived macrophages mediate chronic graft-versus-host disease. J Clin Invest. 2014;124:4266–80.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Taylor DK, Mittereder N, Kuta E, Delaney T, Burwell T, Dacosta K, et al. T follicular helper-like cells contribute to skin fibrosis. Sci Transl Med. 2018;10.

  31. Bucher C, Koch L, Vogtenhuber C, Goren E, Munger M, Panoskaltsis-Mortari A, et al. IL-21 blockade reduces graft-versus-host disease mortality by supporting inducible T regulatory cell generation. Blood. 2009;114:5375–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Knipe RS, Tager AM, Liao JK. The Rho kinases: critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis. Pharmacol Rev. 2015;67:103–17.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Zanin-Zhorov A, Blazar BR. ROCK2, a critical regulator of immune modulation and fibrosis has emerged as a therapeutic target in chronic graft-versus-host disease. Clin Immunol. 2021;230:108823.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Nassereddine S, Rafei H, Elbahesh E, Tabbara I. Acute graft versus host disease: a comprehensive review. Anticancer Res. 2017;37:1547–55.

    Article  CAS  PubMed  Google Scholar 

  35. Hofmeister CC, Quinn A, Cooke KR, Stiff P, Nickoloff B, Ferrara JL. Graft-versus-host disease of the skin: life and death on the epidermal edge. Biol Blood Marrow Transplant. 2004;10:366–72.

    Article  PubMed  Google Scholar 

  36. Gale RP, Bortin MM, van Bekkum DW, Biggs JC, Dicke KA, Gluckman E, et al. Risk factors for acute graft-versus-host disease. Br J Haematol. 1987;67:397–406.

    Article  CAS  PubMed  Google Scholar 

  37. Gupta A, Punatar S, Gawande J, Mathew L, Bagal B, Kannan S, et al. Risk factors, pattern and clinical outcome of acute graft versus host disease in acute leukemia patients undergoing allogeneic stem cell transplant. Indian J Hematol Blood Transfus. 2015;31:404–12.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Jagasia M, Arora M, Flowers ME, Chao NJ, McCarthy PL, Cutler CS, et al. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood. 2012;119:296–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lazaryan A, Weisdorf DJ, DeFor T, Brunstein CG, MacMillan ML, Bejanyan N, et al. Risk factors for acute and chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation with umbilical cord blood and matched sibling donors. Biol Blood Marrow Transplant. 2016;22:134–40.

    Article  PubMed  Google Scholar 

  40. Lee SE, Cho BS, Kim JH, Yoon JH, Shin SH, Yahng SA, et al. Risk and prognostic factors for acute GVHD based on NIH consensus criteria. Bone Marrow Transplant. 2013;48:587–92.

    Article  PubMed  Google Scholar 

  41. Nash RA, Pepe MS, Storb R, Longton G, Pettinger M, Anasetti C, et al. Acute graft-versus-host disease: analysis of risk factors after allogeneic marrow transplantation and prophylaxis with cyclosporine and methotrexate. Blood. 1992;80:1838–45.

    Article  CAS  PubMed  Google Scholar 

  42. Ilyas M, Colegio OR, Kaplan B, Sharma A. Cutaneous toxicities from transplantation-related medications. Am J Transplant. 2017;17:2782–9.

    Article  CAS  PubMed  Google Scholar 

  43. Strong Rodrigues K, Oliveira-Ribeiro C, de Abreu Fiuza Gomes S, Knobler R. Cutaneous graft-versus-host disease: diagnosis and treatment. Am J Clin Dermatol. 2018;19:33–50.

    Article  PubMed  Google Scholar 

  44. Byun HJ, Yang JI, Kim BK, Cho KH. Clinical differentiation of acute cutaneous graft-versus-host disease from drug hypersensitivity reactions. J Am Acad Dermatol. 2011;65:726–32.

    Article  PubMed  Google Scholar 

  45. Hunjan MK, Nowsheen S, Ramos-Rodriguez AJ, Hashmi SK, Bridges AG, Lehman JS, et al. Clinical and histopathological spectrum of toxic erythema of chemotherapy in patients who have undergone allogeneic hematopoietic cell transplantation. Hematol Oncol Stem Cell Ther. 2019;12:19–25.

    Article  CAS  PubMed  Google Scholar 

  46. Matsushita T, Hasegawa M, Shirasaki F, Fujimoto M, Yamazaki H, Sato S, et al. A case of acute cutaneous graft-versus-host disease mimicking psoriasis vulgaris. Dermatology. 2008;216:64–7.

    Article  PubMed  Google Scholar 

  47. Surjana D, Robertson I, Kennedy G, James D, Weedon D. Acute cutaneous graft-versus-host disease resembling type II (atypical adult) pityriasis rubra pilaris. Australas J Dermatol. 2015;56:e21–3.

    Article  PubMed  Google Scholar 

  48. Huang J, Pol-Rodriguez M, Silvers D, Garzon MC. Acquired ichthyosis as a manifestation of acute cutaneous graft-versus-host disease. Pediatr Dermatol. 2007;24:49–52.

    Article  CAS  PubMed  Google Scholar 

  49. Levine JE, Braun TM, Harris AC, Holler E, Taylor A, Miller H, et al. A prognostic score for acute graft-versus-host disease based on biomarkers: a multicentre study. Lancet Haematol. 2015;2:e21–9.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Saliba RM, de Lima M, Giralt S, Andersson B, Khouri IF, Hosing C, et al. Hyperacute GVHD: risk factors, outcomes, and clinical implications. Blood. 2007;109:2751–8.

    Article  CAS  PubMed  Google Scholar 

  51. Hong KT, Kang HJ, Kim NH, Kim MS, Lee JW, Kim H, et al. Peri-engraftment syndrome in allogeneic hematopoietic SCT. Bone Marrow Transplant. 2013;48:523–8.

    Article  CAS  PubMed  Google Scholar 

  52. Spitzer TR. Engraftment syndrome: double-edged sword of hematopoietic cell transplants. Bone Marrow Transplant. 2015;50:469–75.

    Article  CAS  PubMed  Google Scholar 

  53. Spitzer TR. Engraftment syndrome following hematopoietic stem cell transplantation. Bone Marrow Transplant. 2001;27:893–8.

    Article  CAS  PubMed  Google Scholar 

  54. Harris AC, Young R, Devine S, Hogan WJ, Ayuk F, Bunworasate U, et al. International, multicenter standardization of acute graft-versus-host disease clinical data collection: a report from the Mount Sinai Acute GVHD International Consortium. Biol Blood Marrow Transplant. 2016;22:4–10.

    Article  PubMed  Google Scholar 

  55. Hausermann P, Walter RB, Halter J, Biedermann BC, Tichelli A, Itin P, et al. Cutaneous graft-versus-host disease: a guide for the dermatologist. Dermatology. 2008;216:287–304.

    Article  PubMed  Google Scholar 

  56. Lehman JS, Dasari S, Damodaran SS, Li M, Hashmi SK, el-Azhary RA, et al. Differentiation of acute graft-versus-host disease from drug reaction in skin by a novel tissue-based biomarker assay. 2023. Preprint at https://assets.researchsquare.com/files/rs-2481845/v1/4325b9da-21cc-4b24-ab0f-4dce6f29b0e9.pdf?c=1673971615.

  57. Lehman JS, Dasari S, Damodaran SS, El-Azhary RA, Gibson LE, Hashmi SK, et al. Differential expression of interferon-induced genes and other tissue-based biomarkers in acute graft-versus-host disease vs. lupus erythematosus in skin. Clin Exp Dermatol. 2019;44:e81–8.

    Article  CAS  PubMed  Google Scholar 

  58. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation. 1974;18:295–304.

    Article  CAS  PubMed  Google Scholar 

  59. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15:825–8.

  60. Rowlings PA, Przepiorka D, Klein JP, Gale RP, Passweg JR, Henslee-Downey PJ, et al. IBMTR Severity Index for grading acute graft-versus-host disease: retrospective comparison with Glucksberg grade. Br J Haematol. 1997;97:855–64.

    Article  CAS  PubMed  Google Scholar 

  61. Moore RA, Waheed A, Burns B, Rule of nines. Treasure Island (FL): StatPearls; 2022.

  62. Tso S, Satchwell F, Moiz H, Hari T, Dhariwal S, Barlow R, et al. Erythroderma (exfoliative dermatitis). Part 1: underlying causes, clinical presentation and pathogenesis. Clin Exp Dermatol. 2021;46:1001–10.

    Article  CAS  PubMed  Google Scholar 

  63. Inamadar AC, Ragunatha S. The rash that becomes an erythroderma. Clin Dermatol. 2019;37:88–98.

    Article  PubMed  Google Scholar 

  64. Miyashiro D, Sanches JA. Erythroderma: a prospective study of 309 patients followed for 12 years in a tertiary center. Sci Rep. 2020;10:9774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Atkinson K, Horowitz MM, Gale RP, van Bekkum DW, Gluckman E, Good RA, et al. Risk factors for chronic graft-versus-host disease after HLA-identical sibling bone marrow transplantation. Blood. 1990;75:2459–64.

    Article  CAS  PubMed  Google Scholar 

  66. Carlens S, Ringden O, Remberger M, Lonnqvist B, Hagglund H, Klaesson S, et al. Risk factors for chronic graft-versus-host disease after bone marrow transplantation: a retrospective single centre analysis. Bone Marrow Transplant. 1998;22:755–61.

    Article  CAS  PubMed  Google Scholar 

  67. Ijaz A, Khan AY, Malik SU, Faridi W, Fraz MA, Usman M, et al. Significant risk of graft-versus-host disease with exposure to checkpoint inhibitors before and after allogeneic transplantation. Biol Blood Marrow Transplant. 2019;25:94–9.

    Article  CAS  PubMed  Google Scholar 

  68. Lv M, Zhang X, Xu L, Wang Y, Yan C, Chen H, et al. Risk factors for chronic graft-versus-host disease after anti-thymocyte globulin-based haploidentical hematopoietic stem cell transplantation in acute myeloid leukemia. Front Med. 2019;13:667–79.

    Article  PubMed  Google Scholar 

  69. Ochs LA, Miller WJ, Filipovich AH, Haake RJ, McGlave PB, Blazar BR, et al. Predictive factors for chronic graft-versus-host disease after histocompatible sibling donor bone marrow transplantation. Bone Marrow Transplant. 1994;13:455–60.

    CAS  PubMed  Google Scholar 

  70. Przepiorka D, Anderlini P, Saliba R, Cleary K, Mehra R, Khouri I, et al. Chronic graft-versus-host disease after allogeneic blood stem cell transplantation. Blood. 2001;98:1695–700.

    Article  CAS  PubMed  Google Scholar 

  71. Remberger M, Beelen DW, Fauser A, Basara N, Basu O, Ringden O. Increased risk of extensive chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplantation using unrelated donors. Blood. 2005;105:548–51.

    Article  CAS  PubMed  Google Scholar 

  72. Remberger M, Kumlien G, Aschan J, Barkholt L, Hentschke P, Ljungman P, et al. Risk factors for moderate-to-severe chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2002;8:674–82.

    Article  PubMed  Google Scholar 

  73. Yang F, Lu D, Hu Y, Huang X, Huang H, Chen J, et al. Risk factors for graft-versus-host disease after transplantation of hematopoietic stem cells from unrelated donors in the china marrow donor program. Ann Transplant. 2017;22:384–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Jacobsohn DA, Kurland BF, Pidala J, Inamoto Y, Chai X, Palmer JM, et al. Correlation between NIH composite skin score, patient-reported skin score, and outcome: results from the Chronic GVHD Consortium. Blood. 2012;120:2545–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Flowers ME, Inamoto Y, Carpenter PA, Lee SJ, Kiem HP, Petersdorf EW, et al. 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. 2011;117:3214–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Grube M, Holler E, Weber D, Holler B, Herr W, Wolff D. Risk factors and outcome of chronic graft-versus-host disease after allogeneic stem cell transplantation-results from a single-center observational study. Biol Blood Marrow Transplant. 2016;22:1781–91.

    Article  PubMed  Google Scholar 

  77. Wojnar J, Giebel S, Holowiecka-Goral A, Krawczyk-Kulis M, Markiewicz M, Wozniczka K, et al. The incidence and risk factors for chronic graft-versus-host-disease. Ann Transplant. 2006;11:14–20.

    PubMed  Google Scholar 

  78. Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant. 2015;21:389–401.e1.

    Article  PubMed  Google Scholar 

  79. Link-Rachner CS, Sockel K, Schuetz C. Established and emerging treatments of skin GvHD. Front Immunol. 2022;13:838494.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Hymes SR, Turner ML, Champlin RE, Couriel DR. Cutaneous manifestations of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2006;12:1101–13.

    Article  PubMed  Google Scholar 

  81. Wang JY, Tabata MM, Pugliese S, Phillips D, Kim J, Weng WK, et al. Pityriasis rubra pilaris-like graft-vs-host disease following allogeneic stem cell transplant in two patients. Clin Case Rep. 2019;7:2491–4.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Penas PF, Jones-Caballero M, Aragues M, Fernandez-Herrera J, Fraga J, Garcia-Diez A. Sclerodermatous graft-vs-host disease: clinical and pathological study of 17 patients. Arch Dermatol. 2002;138:924–34.

    Article  PubMed  Google Scholar 

  83. Schaffer JV, McNiff JM, Seropian S, Cooper DL, Bolognia JL. Lichen sclerosus and eosinophilic fasciitis as manifestations of chronic graft-versus-host disease: expanding the sclerodermoid spectrum. J Am Acad Dermatol. 2005;53:591–601.

    Article  PubMed  Google Scholar 

  84. Lee SJ, Wolff D, Kitko C, Koreth J, Inamoto Y, Jagasia M, et al. Measuring therapeutic response in chronic graft-versus-host disease. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IV. The 2014 Response Criteria Working Group report. Biol Blood Marrow Transplant. 2015;21:984–99.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Lee SJ. Classification systems for chronic graft-versus-host disease. Blood. 2017;129:30–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Mitchell SA, Jacobsohn D, Thormann Powers KE, Carpenter PA, Flowers ME, Cowen EW, et al. A multicenter pilot evaluation of the National Institutes of Health chronic graft-versus-host disease (cGVHD) therapeutic response measures: feasibility, interrater reliability, and minimum detectable change. Biol Blood Marrow Transplant. 2011;17:1619–29.

    Article  PubMed  PubMed Central  Google Scholar 

  87. El-Jawahri A, Li S, Antin JH, Spitzer TR, Armand PA, Koreth J, et al. Improved treatment-related mortality and overall survival of patients with grade IV acute GVHD in the modern years. Biol Blood Marrow Transplant. 2016;22:910–8.

    Article  PubMed  Google Scholar 

  88. Hahn T, McCarthy PL Jr., Hassebroek A, Bredeson C, Gajewski JL, Hale GA, et al. Significant improvement in survival after allogeneic hematopoietic cell transplantation during a period of significantly increased use, older recipient age, and use of unrelated donors. J Clin Oncol. 2013;31:2437–49.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Garnett C, Apperley JF, Pavlu J. Treatment and management of graft-versus-host disease: improving response and survival. Ther Adv Hematol. 2013;4:366–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Carpenter PA, Kitko CL, Elad S, Flowers ME, Gea-Banacloche JC, Halter JP, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: V. The 2014 Ancillary Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant. 2015;21:1167–87.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Mukherjee A, Ekinci E, Scholoff A, Obi G, Vu N, Carrum G, et al. Voriconazole photosensitivity causes apparent graft-versus-host disease exacerbation. Bone Marrow Transplant. 2019;54:323–5.

    Article  PubMed  Google Scholar 

  92. El-Jawahri A. What else do I need to worry about when treating graft-versus-host disease? Hematology Am Soc Hematol Educ Program. 2021;2021:655–61.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Dignan FL, Clark A, Amrolia P, Cornish J, Jackson G, Mahendra P, et al. Diagnosis and management of acute graft-versus-host disease. Br J Haematol. 2012;158:30–45.

    Article  CAS  PubMed  Google Scholar 

  94. Kragballe K. Topical corticosteroids: mechanisms of action. Acta Derm Venereol Suppl. 1989;151:7–10. discussion 47-52.

    CAS  Google Scholar 

  95. Wolff D, Gerbitz A, Ayuk F, Kiani A, Hildebrandt GC, Vogelsang GB, et al. Consensus conference on clinical practice in chronic graft-versus-host disease (GVHD): first-line and topical treatment of chronic GVHD. Biol Blood Marrow Transplant. 2010;16:1611–28.

    Article  PubMed  Google Scholar 

  96. Choi CJ, Nghiem P. Tacrolimus ointment in the treatment of chronic cutaneous graft-vs-host disease: a case series of 18 patients. Arch Dermatol. 2001;137:1202–6.

    Article  CAS  PubMed  Google Scholar 

  97. Rosmarin D, Passeron T, Pandya AG, Grimes P, Harris JE, Desai SR, et al. Two phase 3, randomized, controlled trials of ruxolitinib cream for vitiligo. N Engl J Med. 2022;387:1445–55.

    Article  CAS  PubMed  Google Scholar 

  98. Markova A, Pan A, Dusza S, Chowdhury A, Kukoyi O, Parales M-A, et al. Interim results of a pilot, prospective, randomized, double-blinded, vehicle- and comparator-controlled trial on safety and efficacy of a topical inhibitor of janus kinase 1/2 (Ruxolitinib INCB018424 Phosphate 1.5% Cream) for non-sclerotic and superficially sclerotic chronic cutaneous graft-versus-host disease. Blood. 2021;138:3915.

    Article  Google Scholar 

  99. MacMillan ML, Weisdorf DJ, Wagner JE, DeFor TE, Burns LJ, Ramsay NK, et al. Response of 443 patients to steroids as primary therapy for acute graft-versus-host disease: comparison of grading systems. Biol Blood Marrow Transplant. 2002;8:387–94.

    Article  CAS  PubMed  Google Scholar 

  100. Mielcarek M, Furlong T, Storer BE, Green ML, McDonald GB, Carpenter PA, et al. Effectiveness and safety of lower dose prednisone for initial treatment of acute graft-versus-host disease: a randomized controlled trial. Haematologica. 2015;100:842–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Pidala J, Onstad L, Martin PJ, Hamilton BK, Cutler C, Kitko CL, et al. Initial therapy for chronic graft-versus-host disease: analysis of practice variation and failure-free survival. Blood Adv. 2021;5:4549–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Hings IM, Filipovich AH, Miller WJ, Blazar BL, McGlave PB, Ramsay NK, et al. Prednisone therapy for acute graft-versus-host disease: short- versus long-term treatment. A prospective randomized trial. Transplantation. 1993;56:577–80.

    Article  CAS  PubMed  Google Scholar 

  103. Bacigalupo A, Milone G, Cupri A, Severino A, Fagioli F, Berger M, et al. Steroid treatment of acute graft-versus-host disease grade I: a randomized trial. Haematologica. 2017;102:2125–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Zeiser R, von Bubnoff N, Butler J, Mohty M, Niederwieser D, Or R, et al. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. N Engl J Med. 2020;382:1800–10.

    Article  PubMed  Google Scholar 

  105. Khandelwal P, Teusink-Cross A, Davies SM, Nelson AS, Dandoy CE, El-Bietar J, et al. Ruxolitinib as salvage therapy in steroid-refractory acute graft-versus-host disease in pediatric hematopoietic stem cell transplant patients. Biol Blood Marrow Transplant. 2017;23:1122–7.

    Article  CAS  PubMed  Google Scholar 

  106. Koc S, Leisenring W, Flowers ME, Anasetti C, Deeg HJ, Nash RA, et al. Therapy for chronic graft-versus-host disease: a randomized trial comparing cyclosporine plus prednisone versus prednisone alone. Blood. 2002;100:48–51.

    Article  CAS  PubMed  Google Scholar 

  107. De Jong CN, Saes L, Klerk CPW, Van der Klift M, Cornelissen JJ, Broers AEC. Etanercept for steroid-refractory acute graft-versus-host disease: a single center experience. PLoS ONE. 2017;12:e0187184.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Ma CKK, Garcia-Cadenas I, Fox ML, Ai S, Nivison-Smith I, Milliken ST, et al. Poor prognosis in patients with steroid refractory acute graft versus host disease treated with etanercept: a multi-centre analysis. Bone Marrow Transplant. 2018;53:1478–82.

    Article  PubMed  Google Scholar 

  109. Park JH, Lee HJ, Kim SR, Song GW, Lee SK, Park SY, et al. Etanercept for steroid-refractory acute graft versus host disease following allogeneic hematopoietic stem cell transplantation. Korean J Intern Med. 2014;29:630–6.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Bordigoni P, Dimicoli S, Clement L, Baumann C, Salmon A, Witz F, et al. Daclizumab, an efficient treatment for steroid-refractory acute graft-versus-host disease. Br J Haematol. 2006;135:382–5.

    Article  CAS  PubMed  Google Scholar 

  111. Przepiorka D, Kernan NA, Ippoliti C, Papadopoulos EB, Giralt S, Khouri I, et al. Daclizumab, a humanized anti-interleukin-2 receptor alpha chain antibody, for treatment of acute graft-versus-host disease. Blood. 2000;95:83–9.

    Article  CAS  PubMed  Google Scholar 

  112. Garcia-Cadenas I, Valcarcel D, Martino R, Pinana JL, Novelli S, Esquirol A, et al. Updated experience with inolimomab as treatment for corticosteroid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant. 2013;19:435–9.

    Article  CAS  PubMed  Google Scholar 

  113. Chakupurakal G, Garcia-Marquez MA, Shimabukuro-Vornhagen A, Theurich S, Holtick U, Hallek M, et al. Immunological effects in patients with steroid-refractory graft-versus-host disease following treatment with basiliximab, a CD25 monoclonal antibody. Eur J Haematol. 2016;97:121–7.

    Article  CAS  PubMed  Google Scholar 

  114. Gomez-Almaguer D, Ruiz-Arguelles GJ, del Carmen Tarin-Arzaga L, Gonzalez-Llano O, Gutierrez-Aguirre H, Cantu-Rodriguez O, et al. Alemtuzumab for the treatment of steroid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant. 2008;14:10–5.

    Article  CAS  PubMed  Google Scholar 

  115. Khandelwal P, Emoto C, Fukuda T, Vinks AA, Neumeier L, Dandoy CE, et al. A prospective study of alemtuzumab as a second-line agent for steroid-refractory acute graft-versus-host disease in pediatric and young adult allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2016;22:2220–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Graziani F, Van Lint MT, Dominietto A, Raiola AM, Di Grazia C, Lamparelli T, et al. Treatment of acute graft versus host disease with low dose-alternate day anti-thymocyte globulin. Haematologica. 2002;87:973–8.

    CAS  PubMed  Google Scholar 

  117. Murata M, Ikegame K, Morishita Y, Ogawa H, Kaida K, Nakamae H, et al. Low-dose thymoglobulin as second-line treatment for steroid-resistant acute GvHD: an analysis of the JSHCT. Bone Marrow Transplant. 2017;52:252–7.

    Article  CAS  PubMed  Google Scholar 

  118. Nishimoto M, Nakamae H, Koh H, Nakamae M, Hirose A, Hayashi Y, et al. Response-guided therapy for steroid-refractory acute GVHD starting with very-low-dose antithymocyte globulin. Exp Hematol. 2015;43:177–9.

    Article  CAS  PubMed  Google Scholar 

  119. Alam N, Atenafu EG, Tse G, Viswabandya A, Gupta V, Kim D, et al. Limited benefit of pentostatin salvage therapy for steroid-refractory grade III-IV acute graft-versus-host disease. Clin Transplant. 2013;27:930–7.

    Article  CAS  PubMed  Google Scholar 

  120. Bolanos-Meade J, Jacobsohn DA, Margolis J, Ogden A, Wientjes MG, Byrd JC, et al. Pentostatin in steroid-refractory acute graft-versus-host disease. J Clin Oncol. 2005;23:2661–8.

    Article  CAS  PubMed  Google Scholar 

  121. Ragon BK, Mehta RS, Gulbis AM, Saliba RM, Chen J, Rondon G, et al. Pentostatin therapy for steroid-refractory acute graft versus host disease: identifying those who may benefit. Bone Marrow Transplant. 2018;53:315–25.

    Article  CAS  PubMed  Google Scholar 

  122. Kim JG, Sohn SK, Kim DH, Lee NY, Suh JS, Lee KS, et al. Different efficacy of mycophenolate mofetil as salvage treatment for acute and chronic GVHD after allogeneic stem cell transplant. Eur J Haematol. 2004;73:56–61.

    Article  CAS  PubMed  Google Scholar 

  123. Nassar A, Elgohary G, Elhassan T, Nurgat Z, Mohamed SY, Aljurf M. Methotrexate for the treatment of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. J Transplant. 2014;2014:980301.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Gergoudis SC, DeFilipp Z, Ozbek U, Sandhu KS, Etra AM, Choe HK, et al. Biomarker-guided preemption of steroid-refractory graft-versus-host disease with alpha-1-antitrypsin. Blood Adv. 2020;4:6098–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Magenau JM, Goldstein SC, Peltier D, Soiffer RJ, Braun T, Pawarode A, et al. alpha(1)-Antitrypsin infusion for treatment of steroid-resistant acute graft-versus-host disease. Blood. 2018;131:1372–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Marcondes AM, Hockenbery D, Lesnikova M, Dinarello CA, Woolfrey A, Gernsheimer T, et al. Response of Steroid-Refractory Acute GVHD to alpha1-Antitrypsin. Biol Blood Marrow Transplant. 2016;22:1596–601.

    Article  CAS  PubMed  Google Scholar 

  127. Carpenter PA, Lowder J, Johnston L, Frangoul H, Khoury H, Parker P, et al. A phase II multicenter study of visilizumab, humanized anti-CD3 antibody, to treat steroid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant. 2005;11:465–71.

    Article  CAS  PubMed  Google Scholar 

  128. Fan S, Huo WX, Yang Y, Shen MZ, Mo XD. Efficacy and safety of ruxolitinib in steroid-refractory graft-versus-host disease: a meta-analysis. Front Immunol. 2022;13:954268.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Chen YB, Perales MA, Li S, Kempner M, Reynolds C, Brown J, et al. Phase 1 multicenter trial of brentuximab vedotin for steroid-refractory acute graft-versus-host disease. Blood. 2017;129:3256–61.

    Article  CAS  PubMed  Google Scholar 

  130. Zaja F, Bacigalupo A, Patriarca F, Stanzani M, Van Lint MT, Fili C, et al. Treatment of refractory chronic GVHD with rituximab: a GITMO study. Bone Marrow Transplant. 2007;40:273–7.

    Article  CAS  PubMed  Google Scholar 

  131. Kim SJ, Lee JW, Jung CW, Min CK, Cho B, Shin HJ, et al. Weekly rituximab followed by monthly rituximab treatment for steroid-refractory chronic graft-versus-host disease: results from a prospective, multicenter, phase II study. Haematologica. 2010;95:1935–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Cutler C, Miklos D, Kim HT, Treister N, Woo SB, Bienfang D, et al. Rituximab for steroid-refractory chronic graft-versus-host disease. Blood. 2006;108:756–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Miklos D, Cutler CS, Arora M, Waller EK, Jagasia M, Pusic I, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood. 2017;130:2243–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Pai CC, Chen M, Mirsoian A, Grossenbacher SK, Tellez J, Ames E, et al. Treatment of chronic graft-versus-host disease with bortezomib. Blood. 2014;124:1677–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Herrera AF, Kim HT, Bindra B, Jones KT, Alyea EP 3rd, Armand P, et al. A phase II study of bortezomib plus prednisone for initial therapy of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2014;20:1737–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Olivieri A, Locatelli F, Zecca M, Sanna A, Cimminiello M, Raimondi R, et al. Imatinib for refractory chronic graft-versus-host disease with fibrotic features. Blood. 2009;114:709–18.

    Article  CAS  PubMed  Google Scholar 

  137. de Masson A, Bouaziz JD, Peffault de Latour R, Wittnebel S, Ribaud P, Rubio MT, et al. Limited efficacy and tolerance of imatinib mesylate in steroid-refractory sclerodermatous chronic GVHD. Blood. 2012;120:5089–90.

    Article  PubMed  Google Scholar 

  138. Baird K, Comis LE, Joe GO, Steinberg SM, Hakim FT, Rose JJ, et al. Imatinib mesylate for the treatment of steroid-refractory sclerotic-type cutaneous chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2015;21:1083–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Pusic I, Rettig MP, DiPersio JF, Bauer S, McFarland K, Gale RP, et al. Phase-1/-2 study of pomalidomide in chronic GvHD. Bone Marrow Transplant. 2016;51:612–4.

    Article  CAS  PubMed  Google Scholar 

  140. Curtis LM, Ostojic A, Venzon DJ, Holtzman NG, Pirsl F, Kuzmina ZJ, et al. A randomized phase 2 trial of pomalidomide in subjects failing prior therapy for chronic graft-versus-host disease. Blood. 2021;137:896–907.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Parker PM, Chao N, Nademanee A, O’Donnell MR, Schmidt GM, Snyder DS, et al. Thalidomide as salvage therapy for chronic graft-versus-host disease. Blood. 1995;86:3604–9.

    Article  CAS  PubMed  Google Scholar 

  142. Browne PV, Weisdorf DJ, DeFor T, Miller WJ, Davies SM, Filipovich A, et al. Response to thalidomide therapy in refractory chronic graft-versus-host disease. Bone Marrow Transplant. 2000;26:865–9.

    Article  CAS  PubMed  Google Scholar 

  143. Holtzman NG, Im A, Ostojic A, Curtis LM, Parsons-Wandell L, Nashed J, et al. Efficacy and safety of baricitinib in refractory chronic graft-versus-host disease (cGVHD): preliminary analysis results of a phase 1/2 study. Blood. 2020;136:1.

    Article  Google Scholar 

  144. Koreth J, Matsuoka K, Kim HT, McDonough SM, Bindra B, Alyea EP 3rd, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med. 2011;365:2055–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Koreth J, Kim HT, Jones KT, Lange PB, Reynolds CG, Chammas MJ, et al. Efficacy, durability, and response predictors of low-dose interleukin-2 therapy for chronic graft-versus-host disease. Blood. 2016;128:130–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Cutler C, Lee SJ, Arai S, Rotta M, Zoghi B, Lazaryan A, et al. Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study. Blood. 2021;138:2278–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Jagasia M, Perales MA, Schroeder MA, Ali H, Shah NN, Chen YB, et al. Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial. Blood. 2020;135:1739–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Zeiser R, Polverelli N, Ram R, Hashmi SK, Chakraverty R, Middeke JM, et al. Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease. N Engl J Med. 2021;385:228–38.

    Article  CAS  PubMed  Google Scholar 

  149. Duan MH, Cao XX, Chang L, Zhou DB. Risk of hepatitis B virus reactivation following ruxolitinib treatment in patients with myeloproliferative neoplasms. Hematology. 2021;26:460–4.

    Article  CAS  PubMed  Google Scholar 

  150. Lussana F, Cattaneo M, Rambaldi A, Squizzato A. Ruxolitinib-associated infections: a systematic review and meta-analysis. Am J Hematol. 2018;93:339–47.

    Article  CAS  PubMed  Google Scholar 

  151. Wathes R, Moule S, Milojkovic D. Progressive multifocal leukoencephalopathy associated with ruxolitinib. N Engl J Med. 2013;369:197–8.

    Article  CAS  PubMed  Google Scholar 

  152. Chin KK, Kim HT, Inyang EA, Ho V, Koreth J, Romee R, et al. Ibrutinib in steroid-refractory chronic graft-versus-host disease, a single-center experience. Transplant Cell Ther. 2021;27:990.e1–e7.

    Article  CAS  PubMed  Google Scholar 

  153. Carpenter PA, Kang HJ, Yoo KH, Zecca M, Cho B, Lucchini G, et al. Ibrutinib treatment of pediatric chronic graft-versus-host disease: primary results from the phase 1/2 iMAGINE Study. Transplant Cell Ther. 2022;28:771.e1–e10.

    Article  CAS  PubMed  Google Scholar 

  154. Paydas S. Management of adverse effects/toxicity of ibrutinib. Crit Rev Oncol Hematol. 2019;136:56–63.

    Article  PubMed  Google Scholar 

  155. Przepiorka D, Le RQ, Ionan A, Li RJ, Wang YH, Gudi R, et al. FDA approval summary: belumosudil for adult and pediatric patients 12 years and older with chronic GvHD after two or more prior lines of systemic therapy. Clin Cancer Res. 2022;28:2488–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Zhou X, Jin N, Wang F, Chen B. Mesenchymal stem cells: a promising way in therapies of graft-versus-host disease. Cancer Cell Int. 2020;20:114.

    Article  PubMed  PubMed Central  Google Scholar 

  157. Bader P, Kuci Z, Bakhtiar S, Basu O, Bug G, Dennis M, et al. Effective treatment of steroid and therapy-refractory acute graft-versus-host disease with a novel mesenchymal stromal cell product (MSC-FFM). Bone Marrow Transplant. 2018;53:852–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Ball LM, Bernardo ME, Roelofs H, van Tol MJ, Contoli B, Zwaginga JJ, et al. Multiple infusions of mesenchymal stromal cells induce sustained remission in children with steroid-refractory, grade III-IV acute graft-versus-host disease. Br J Haematol. 2013;163:501–9.

    Article  CAS  PubMed  Google Scholar 

  159. Dotoli GM, De Santis GC, Orellana MD, de Lima Prata K, Caruso SR, Fernandes TR, et al. Mesenchymal stromal cell infusion to treat steroid-refractory acute GvHD III/IV after hematopoietic stem cell transplantation. Bone Marrow Transplant. 2017;52:859–62.

    Article  CAS  PubMed  Google Scholar 

  160. Fernandez-Maqueda C, Gonzalo-Daganzo R, Regidor C, Martin-Donaire T, Sanchez R, Bueno JL, et al. Mesenchymal stromal cells for steroid-refractory acute GvHD. Bone Marrow Transplant. 2017;52:1577–9.

    Article  CAS  PubMed  Google Scholar 

  161. Introna M, Lucchini G, Dander E, Galimberti S, Rovelli A, Balduzzi A, et al. Treatment of graft versus host disease with mesenchymal stromal cells: a phase I study on 40 adult and pediatric patients. Biol Blood Marrow Transplant. 2014;20:375–81.

    Article  PubMed  Google Scholar 

  162. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008;371:1579–86.

    Article  PubMed  Google Scholar 

  163. Muroi K, Miyamura K, Ohashi K, Murata M, Eto T, Kobayashi N, et al. Unrelated allogeneic bone marrow-derived mesenchymal stem cells for steroid-refractory acute graft-versus-host disease: a phase I/II study. Int J Hematol. 2013;98:206–13.

    Article  CAS  PubMed  Google Scholar 

  164. Muroi K, Miyamura K, Okada M, Yamashita T, Murata M, Ishikawa T, et al. Bone marrow-derived mesenchymal stem cells (JR-031) for steroid-refractory grade III or IV acute graft-versus-host disease: a phase II/III study. Int J Hematol. 2016;103:243–50.

    Article  CAS  PubMed  Google Scholar 

  165. Perez-Simon JA, Lopez-Villar O, Andreu EJ, Rifon J, Muntion S, Diez Campelo M, et al. Mesenchymal stem cells expanded in vitro with human serum for the treatment of acute and chronic graft-versus-host disease: results of a phase I/II clinical trial. Haematologica. 2011;96:1072–6.

    Article  PubMed  PubMed Central  Google Scholar 

  166. Resnick IB, Barkats C, Shapira MY, Stepensky P, Bloom AI, Shimoni A, et al. Treatment of severe steroid resistant acute GVHD with mesenchymal stromal cells (MSC). Am J Blood Res. 2013;3:225–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Salmenniemi U, Itala-Remes M, Nystedt J, Putkonen M, Niittyvuopio R, Vettenranta K, et al. Good responses but high TRM in adult patients after MSC therapy for GvHD. Bone Marrow Transplant. 2017;52:606–8.

    Article  CAS  PubMed  Google Scholar 

  168. Sanchez-Guijo F, Caballero-Velazquez T, Lopez-Villar O, Redondo A, Parody R, Martinez C, et al. Sequential third-party mesenchymal stromal cell therapy for refractory acute graft-versus-host disease. Biol Blood Marrow Transplant. 2014;20:1580–5.

    Article  PubMed  Google Scholar 

  169. Servais S, Baron F, Lechanteur C, Seidel L, Selleslag D, Maertens J, et al. Infusion of bone marrow derived multipotent mesenchymal stromal cells for the treatment of steroid-refractory acute graft-versus-host disease: a multicenter prospective study. Oncotarget. 2018;9:20590–604.

    Article  PubMed  PubMed Central  Google Scholar 

  170. von Dalowski F, Kramer M, Wermke M, Wehner R, Rollig C, Alakel N, et al. Mesenchymal stromal cells for treatment of acute steroid-refractory graft versus host disease: clinical responses and long-term outcome. Stem Cells. 2016;34:357–66.

    Article  Google Scholar 

  171. Boberg E, von Bahr L, Afram G, Lindstrom C, Ljungman P, Heldring N, et al. Treatment of chronic GvHD with mesenchymal stromal cells induces durable responses: a phase II study. Stem Cells Transl Med. 2020;9:1190–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Li Y, Hao J, Hu Z, Yang YG, Zhou Q, Sun L, et al. Current status of clinical trials assessing mesenchymal stem cell therapy for graft versus host disease: a systematic review. Stem Cell Res Ther. 2022;13:93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Drexler B, Buser A, Infanti L, Stehle G, Halter J, Holbro A. Extracorporeal photopheresis in graft-versus-host disease. Transfus Med Hemother. 2020;47:214–25.

    Article  PubMed  PubMed Central  Google Scholar 

  174. Sakellari I, Gavriilaki E, Batsis I, Mallouri D, Panteliadou AK, Lazaridou A, et al. Favorable impact of extracorporeal photopheresis in acute and chronic graft versus host disease: prospective single-center study. J Clin Apher. 2018;33:654–60.

    Article  PubMed  Google Scholar 

  175. Nygaard M, Karlsmark T, Andersen NS, Schjodt IM, Petersen SL, Friis LS, et al. Extracorporeal photopheresis is a valuable treatment option in steroid-refractory or steroid-dependent acute graft versus host disease-experience with three different approaches. Bone Marrow Transplant. 2019;54:150–4.

    Article  PubMed  Google Scholar 

  176. Niittyvuopio R, Juvonen E, Heiskanen J, Lindstrom V, Nihtinen A, Sahlstedt L, et al. Extracorporeal photopheresis in the treatment of acute graft-versus-host disease: a single-center experience. Transfusion. 2018;58:1973–9.

    Article  CAS  PubMed  Google Scholar 

  177. Malagola M, Cancelli V, Skert C, Leali PF, Ferrari E, Tiburzi A, et al. Extracorporeal photopheresis for treatment of acute and chronic graft versus host disease: an Italian multicentric retrospective analysis on 94 patients on Behalf of the Gruppo Italiano Trapianto di Midollo Osseo. Transplantation. 2016;100:e147–55.

    Article  PubMed  Google Scholar 

  178. Hautmann AH, Wolff D, Hahn J, Edinger M, Schirmer N, Ammer J, et al. Extracorporeal photopheresis in 62 patients with acute and chronic GVHD: results of treatment with the COBE Spectra System. Bone Marrow Transplant. 2013;48:439–45.

    Article  CAS  PubMed  Google Scholar 

  179. Hackstein H, Amoros JJ, Bein G, Woessmann W. Successful use of miniphotopheresis for the treatment of graft-versus-host disease. Transfusion. 2014;54:2022–7.

    Article  PubMed  Google Scholar 

  180. Cid J, Carbasse G, Suarez-Lledo M, Moreno DF, Martinez C, Gutierrez-Garcia G, et al. Efficacy and safety of one-day offline extracorporeal photopheresis schedule processing one total blood volume for treating patients with graft-versus-host disease. Transfusion. 2019;59:2636–42.

    Article  PubMed  Google Scholar 

  181. Jagasia M, Greinix H, Robin M, Das-Gupta E, Jacobs R, Savani BN, et al. Extracorporeal photopheresis versus anticytokine therapy as a second-line treatment for steroid-refractory acute GVHD: a multicenter comparative analysis. Biol Blood Marrow Transplant. 2013;19:1129–33.

    Article  CAS  PubMed  Google Scholar 

  182. Malik MI, Litzow M, Hogan W, Patnaik M, Murad MH, Prokop LJ, et al. Extracorporeal photopheresis for chronic graft-versus-host disease: a systematic review and meta-analysis. Blood Res. 2014;49:100–6.

    Article  PubMed  PubMed Central  Google Scholar 

  183. Ballester-Sanchez R, Navarro-Mira MA, de Unamuno-Bustos B, Pujol-Marco C, Sanz-Caballer J, Botella-Estrada R. The role of phototherapy in cutaneous chronic graft-vs-host disease: a retrospective study and review of the literature. Actas Dermosifiliogr. 2015;106:651–7.

    CAS  PubMed  Google Scholar 

  184. Bonanomi S, Balduzzi A, Tagliabue A, Biagi E, Rovelli A, Corti P, et al. Bath PUVA therapy in pediatric patients with drug-resistant cutaneous graft-versus-host disease. Bone Marrow Transplant. 2001;28:631–2.

    Article  CAS  PubMed  Google Scholar 

  185. Eppinger T, Ehninger G, Steinert M, Niethammer D, Dopfer R. 8-Methoxypsoralen and ultraviolet A therapy for cutaneous manifestations of graft-versus-host disease. Transplantation. 1990;50:807–11.

    Article  CAS  PubMed  Google Scholar 

  186. Ghoreschi K, Thomas P, Penovici M, Ullmann J, Sander CA, Ledderose G, et al. PUVA-bath photochemotherapy and isotretinoin in sclerodermatous graft-versus-host disease. Eur J Dermatol. 2008;18:667–70.

    CAS  PubMed  Google Scholar 

  187. Hoffner MV, Carrizosa Esquivel A, Pulpillo Ruiz A, Herrera Saval A, Conejo-Mir J, Camacho FM. Two cases of cutaneous chronic graft versus host disease in treatment with psoralen plus ultraviolet-A-bath photochemotherapy. J Drugs Dermatol. 2009;8:1027–9.

    PubMed  Google Scholar 

  188. Jampel RM, Farmer ER, Vogelsang GB, Wingard J, Santos GW, Morison WL. PUVA therapy for chronic cutaneous graft-vs-host disease. Arch Dermatol. 1991;127:1673–8.

    Article  CAS  PubMed  Google Scholar 

  189. Leiter U, Kaskel P, Krahn G, Gottlober P, Bunjes D, Peter RU, et al. Psoralen plus ultraviolet-A-bath photochemotherapy as an adjunct treatment modality in cutaneous chronic graft versus host disease. Photodermatol Photoimmunol Photomed. 2002;18:183–90.

    Article  CAS  PubMed  Google Scholar 

  190. Vogelsang GB, Wolff D, Altomonte V, Farmer E, Morison WL, Corio R, et al. Treatment of chronic graft-versus-host disease with ultraviolet irradiation and psoralen (PUVA). Bone Marrow Transplant. 1996;17:1061–7.

    CAS  PubMed  Google Scholar 

  191. Schlaak M, Schwind S, Wetzig T, Maschke J, Treudler R, Basara N, et al. UVA (UVA-1) therapy for the treatment of acute GVHD of the skin. Bone Marrow Transplant. 2010;45:1741–8.

    Article  CAS  PubMed  Google Scholar 

  192. Feldstein JV, Bolanos-Meade J, Anders VL, Abuav R. Narrowband ultraviolet B phototherapy for the treatment of steroid-refractory and steroid-dependent acute graft-versus-host disease of the skin. J Am Acad Dermatol. 2011;65:733–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. George L, Peter D, Chopra M, George B, Abraham A, Mathews V, et al. Efficacy of narrow band UVB in the treatment of cutaneous GvHD: an Indian experience. Bone Marrow Transplant. 2016;51:988–90.

    Article  CAS  PubMed  Google Scholar 

  194. Grundmann-Kollmann M, Martin H, Ludwig R, Klein S, Boehncke WH, Hoelzer D, et al. Narrowband UV-B phototherapy in the treatment of cutaneous graft versus host disease. Transplantation. 2002;74:1631–4.

    Article  CAS  PubMed  Google Scholar 

  195. Snyder AN, Wine Lee L, Jaroscak JJ, Donahoo LB, Hudspeth M. Outcomes using narrowband UVB phototherapy for acute cutaneous graft versus host disease in pediatric allogeneic hematopoietic stem cell transplant recipients. J Pediatr Hematol Oncol. 2021;43:e151–3.

    Article  CAS  PubMed  Google Scholar 

  196. Brazzelli V, Grasso V, Muzio F, Moggio E, Zecca M, Locatelli F, et al. Narrowband ultraviolet B phototherapy in the treatment of cutaneous graft-versus-host disease in oncohaematological paediatric patients. Br J Dermatol. 2010;162:404–9.

    Article  CAS  PubMed  Google Scholar 

  197. Enk CD, Elad S, Vexler A, Kapelushnik J, Gorodetsky R, Kirschbaum M. Chronic graft-versus-host disease treated with UVB phototherapy. Bone Marrow Transplant. 1998;22:1179–83.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr. Bipin Savani for useful discussion. This study was partially supported by a Patterson Foundation Seary Clinical Investigator Award, an American Society of Hematology Scholar Award, an Edward P. Evans Foundation Young Investigator Award, a Conquer Cancer Foundation American Society of Clinical Oncology Career Development Grant, and an American Cancer Society Clinician Scientist Development Grant, Vanderbilt Ingram Cancer Center CCSG (to TKK). ERT was supported by a Career Development Award from the United States Department of Veterans Affairs Clinical Sciences R&D Service (IK2 CX001785).

Author information

Author notes

  1. These authors contributed equally: Junshik Hong, Johnathan Fraebel.

Authors and Affiliations

  1. Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea

    Junshik Hong

  2. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea

    Junshik Hong

  3. Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Junshik Hong, Johnathan Fraebel, Yenny Yang & Tae Kon Kim

  4. Veterans Affairs Tennessee Valley Health Care, Nashville, TN, USA

    Eric Tkacyk & Tae Kon Kim

  5. Department of Dermatology, Vanderbilt University Medical Center, Nashville, TN, USA

    Eric Tkacyk

  6. Monroe Carell Jr Children’s Hospital, Vanderbilt Division of Pediatric Hematology-Oncology, Nashville, TN, USA

    Carrie Kitko

  7. Vanderbilt-Ingram Cancer Center, Nashville, TN, USA

    Carrie Kitko & Tae Kon Kim

  8. Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA

    Tae Kon Kim

Authors
  1. Junshik Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Johnathan Fraebel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yenny Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eric Tkacyk
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Carrie Kitko
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tae Kon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JH was responsible for conceiving the idea of the review, conducting the literature review, writing the manuscript, and both creating and identifying the figures used in the paper. JF was responsible for conducting the literature review, writing the manuscript, and both creating and identifying the figures used in the paper. YY, ET, CK reviewed the above work, provided important revisions to the manuscript, contributed to the literature search, and offered input regarding the design and scope of topics reviewed. TKK was responsible for conceiving the idea behind the review, contributed to the literature search, reviewed, and provided revisions for the manuscript, and offered input regarding the design and scope of topics reviewed.

Corresponding author

Correspondence to Tae Kon Kim.

Ethics declarations

Competing interests

TKK has received a research funding from Nextcure, that is not relevant to this manuscript. TKK is a consultant for Agenus and Immunobiome. ERT has previously received as a consultant for Incyte. CLK has serviced on an advisory board for Horizon Therapeutics. Other authors declare no competing financial interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hong, J., Fraebel, J., Yang, Y. et al. Understanding and treatment of cutaneous graft-versus-host-disease. Bone Marrow Transplant 58, 1298–1313 (2023). https://doi.org/10.1038/s41409-023-02109-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-023-02109-x

Search

Advanced search

Quick links