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:

Ocular graft-versus-host disease after hematopoietic cell transplantation: Expert review from the Late Effects and Quality of Life Working Committee of the CIBMTR and Transplant Complications Working Party of the EBMT

Abstract

Ocular graft-versus-host disease (GVHD) occurs in more than half of patients who develop chronic GVHD after allogeneic hematopoietic cell transplantation (HCT), causing prolonged morbidity, which affects activities of daily living and quality of life. Here we provide an expert review of ocular GVHD in a collaboration between transplant physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Recent updates in ocular GVHD, regarding pathophysiology, preclinical models, risk factors, prevention, screening, diagnosis, response criteria, evaluation measures, and treatment are discussed in this review. Ocular GVHD has at least three biological processes: lacrimal gland dysfunction, meibomian gland dysfunction, and corneoconjunctival inflammation. Preclinical models have found several novel pathogenic mechanisms, including renin angiotensin system and endoplasmic reticulum stress signaling that can be targeted by therapeutic agents. Many studies have identified reliable tests for establishing diagnosis and response assessment of ocular GVHD. Efficacy of systemic and topical treatment for ocular GVHD is summarized. It is important for all health professionals taking care of HCT recipients to have adequate knowledge of ocular GVHD for optimal care.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Similar content being viewed by others

References

  1. Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2003;9:215–33.

    Article  CAS  PubMed  Google Scholar 

  2. Tichelli A, Duell T, Weiss M, Socie G, Ljungman P, Cohen A, et al. Late-onset keratoconjunctivitis sicca syndrome after bone marrow transplantation: incidence and risk factors. European Group or Blood and Marrow Transplantation (EBMT) Working Party on Late Effects. Bone Marrow Transplant. 1996;17:1105–11.

    CAS  PubMed  Google Scholar 

  3. Ogawa Y, Okamoto S, Wakui M, Watanabe R, Yamada M, Yoshino M, et al. Dry eye after haematopoietic stem cell transplantation. Br J Ophthalmol. 1999;83:1125–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Flowers ME, Parker PM, Johnston LJ, Matos AV, Storer B, Bensinger WI, et al. Comparison of chronic graft-versus-host disease after transplantation of peripheral blood stem cells versus bone marrow in allogeneic recipients: long-term follow-up of a randomized trial. Blood. 2002;100:415–9.

    Article  CAS  PubMed  Google Scholar 

  5. Westeneng AC, Hettinga Y, Lokhorst H, Verdonck L, van Dorp S, Rothova A. Ocular graft-versus-host disease after allogeneic stem cell transplantation. Cornea. 2010;29:758–63.

    Article  PubMed  Google Scholar 

  6. Couriel D, Carpenter PA, Cutler C, Bolanos-Meade J, Treister NS, Gea-Banacloche J, et al. Ancillary therapy and supportive care of chronic graft-versus-host disease: national institutes of health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: V. Ancillary Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant. 2006;12:375–96.

    Article  PubMed  Google Scholar 

  7. 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.

    Article  PubMed  Google Scholar 

  8. Dietrich-Ntoukas T, Cursiefen C, Westekemper H, Eberwein P, Reinhard T, Bertz, et al. Diagnosis and treatment of ocular chronic graft-versus-host disease: report from the German-Austrian-Swiss Consensus Conference on Clinical Practice in chronic GVHD. Cornea. 2012;31:299–310.

    Article  PubMed  Google Scholar 

  9. Shikari H, Amparo F, Saboo U, Dana R. Onset of ocular graft-versus-host disease symptoms after allogeneic hematopoietic stem cell transplantation. Cornea. 2015;34:243–7.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Jacobs R, Tran U, Chen H, Kassim A, Engelhardt BG, Greer JP, et al. Prevalence and risk factors associated with development of ocular GVHD defined by NIH consensus criteria. Bone Marrow Transplant. 2012;47:1470–3.

    Article  CAS  PubMed  Google Scholar 

  11. Craig JP, Nichols KK, Akpek EK, Caffery B, Dua HS, Joo CK, et al. TFOS DEWS II definition and classification report. Ocul Surf. 2017;15:276–83.

    Article  PubMed  Google Scholar 

  12. Cooke KR, Luznik L, Sarantopoulos S, Hakim FT, Jagasia M, Fowler DH, et al. 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. 2017;23:211–34.

    Article  PubMed  Google Scholar 

  13. Ogawa Y, Kuwana M, Yamazaki K, Mashima Y, Yamada M, Mori T, et al. Periductal area as the primary site for T-cell activation in lacrimal gland chronic graft-versus-host disease. Invest Ophthalmol Vis Sci. 2003;44:1888–96.

    Article  PubMed  Google Scholar 

  14. Ogawa Y, Yamazaki K, Kuwana M, Mashima Y, Nakamura Y, Ishida S, et al. A significant role of stromal fibroblasts in rapidly progressive dry eye in patients with chronic GVHD. Invest Ophthalmol Vis Sci. 2001;42:111–9.

    CAS  PubMed  Google Scholar 

  15. Kusne Y, Temkit M, Khera N, Patel DR, Shen JF. Conjunctival subepithelial fibrosis and meibomian gland atrophy in ocular graft-versus-host disease. Ocul Surf. 2017;15:784–8.

    Article  PubMed  Google Scholar 

  16. Jabs DA, Wingard J, Green WR, Farmer ER, Vogelsang G, Saral R. The eye in bone marrow transplantation. III. Conjunctival graft-vs-host disease. Arch Ophthalmol. 1989;107:1343–8.

    Article  CAS  PubMed  Google Scholar 

  17. Herretes S, Ross DB, Duffort S, Barreras H, Yaohong T, Saeed AM, et al. Recruitment of donor T Cells to the eyes during ocular GVHD in recipients of MHC-matched allogeneic hematopoietic stem cell transplants. Invest Ophthalmol Vis Sci. 2015;56:2348–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sakimoto T, Ohnishi T, Ishimori A. Significance of ectodomain shedding of TNF receptor 1 in ocular surface. Invest Ophthalmol Vis Sci. 2014;55:2419–23.

    Article  CAS  PubMed  Google Scholar 

  19. Schargus M, Meyer-ter-Vehn T, Menrath J, Grigoleit GU, Geerling G. Correlation between tear film osmolarity and the disease score of the international chronic ocular graft-versus-host-disease consensus group in hematopoietic stem cell transplantation patients. Cornea. 2015;34:911–6.

    Article  PubMed  Google Scholar 

  20. Na KS, Yoo YS, Hwang KY, Mok JW, Joo CK. Tear osmolarity and ocular surface parameters as diagnostic markers of ocular graft-versus-host disease. Am J Ophthalmol. 2015;160:143–9 e141.

    Article  PubMed  Google Scholar 

  21. Jung JW, Han SJ, Song MK, Kim TI, Kim EK, Min YH, et al. Tear cytokines as biomarkers for chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2015;21:2079–85.

    Article  CAS  PubMed  Google Scholar 

  22. Sapna Tibrewal, Joy Sarkar, Sarmad H. Jassim, Sonal Gandhi, Snehal Sonawane, Shweta Chaudhary, Yong-Soo Byun, Yair Ivanir, Joelle Hallak, John H. Horner, Martin Newcomb, Sandeep Jain, (2013) Tear Fluid Extracellular DNA: Diagnostic and Therapeutic Implications in Dry Eye Disease. Investigative Opthalmology & Visual Science 54:8051

    Article  CAS  Google Scholar 

  23. He J, Ogawa Y, Mukai S, Saijo-Ban Y, Kamoi M, Uchino M, et al. In vivo confocal microscopy evaluation of ocular surface with graft-versus-host disease-related dry eye disease. Sci Rep. 2017;7:10720.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Perez RL, Perez-Simon JA, Caballero-Velazquez T, Flores T, Carrancio S, Herrero C, et al. Limbus damage in ocular graft-versus-host disease. Biol Blood Marrow Transplant. 2011;17:270–3.

    Article  PubMed  Google Scholar 

  25. Ogawa Y, Morikawa S, Okano H, Mabuchi Y, Suzuki S, Yaguchi T, et al. MHC-compatible bone marrow stromal/stem cells trigger fibrosis by activating host T cells in a scleroderma mouse model. eLife. 2016;5:e09394.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Yamane M, Ogawa Y, Mukai S, Yaguchi S, Kamijuku H, Inaba T, et al. Functional role of lacrimal gland fibroblasts in a mouse model of chronic graft-versus-host disease. Cornea. 2018;37:102–8.

    Article  PubMed  Google Scholar 

  27. Yaguchi S, Ogawa Y, Shimmura S, Kawakita T, Hatou S, Satofuka S, et al. Angiotensin II type 1 receptor antagonist attenuates lacrimal gland, lung, and liver fibrosis in a murine model of chronic graft-versus-host disease. PLoS ONE. 2013;8:e64724.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mukai S, Ogawa Y, Urano F, Kudo-Saito C, Kawakami Y, Tsubota K. Novel treatment of chronic graft-versus-host disease in mice using the er stress reducer 4-phenylbutyric acid. Sci Rep. 2017;7:41939.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ogawa Y, He H, Mukai S, Imada T, Nakamura S, Su CW, et al. Heavy chain-hyaluronan/pentraxin 3 from amniotic membrane suppresses inflammation and scarring in murine lacrimal gland and conjunctiva of chronic graft-versus-host disease. Sci Rep. 2017;7:42195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Na KS, Yoo YS, Mok JW, Lee JW, Joo CK. Incidence and risk factors for ocular GVHD after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2015;50:1459–64.

    Article  CAS  PubMed  Google Scholar 

  31. Arai S, Jagasia M, Storer B, Chai X, Pidala J, Cutler C, et al. Global and organ-specific chronic graft-versus-host disease severity according to the 2005 NIH Consensus Criteria. Blood. 2011;118:4242–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Uchino M, Ogawa Y, Uchino Y, Mori T, Okamoto S, Tsubota K. Comparison of stem cell sources in the severity of dry eye after allogeneic haematopoietic stem cell transplantation. Br J Ophthalmol. 2012;96:34–37.

    Article  PubMed  Google Scholar 

  33. Kamoi M, Ogawa Y, Uchino M, Tatematsu Y, Mori T, Okamoto S, et al. Donor-recipient gender difference affects severity of dry. Eye Hematop stem Cell Transplant Eye. 2011;25:860–5.

    CAS  Google Scholar 

  34. Wang JC, Teichman JC, Mustafa M, O’Donnell H, Broady R, Yeung SN. Risk factors for the development of ocular graft-versus-host disease (GVHD) Dry Eye syndrome in patients with chronic GVHD. Br J Ophthalmol. 2015;99:1514–8.

    Article  PubMed  Google Scholar 

  35. Pathak M, Diep PP, Lai X, Brinch L, Ruud E, Drolsum L. Ocular findings and ocular graft-versus-host disease after allogeneic stem cell transplantation without total body irradiation. Bone Marrow Transplant. 2018;53:863–72.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Wolffsohn JS, Arita R, Chalmers R, Djalilian A, Dogru M, Dumbleton K, et al. TFOS DEWS II diagnostic methodology report. Ocul Surf. 2017;15:539–74.

    Article  PubMed  Google Scholar 

  37. Curtis LM, Datiles MB 3rd, Steinberg SM, Mitchell SA, Bishop RJ, Cowen EW, et al. Predictive models for ocular chronic graft-versus-host disease diagnosis and disease activity in transplant clinical practice. Haematologica. 2015;100:1228–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Nichols KK, Mitchell GL, Zadnik K. The repeatability of clinical measurements of dry eye. Cornea. 2004;23:272–85.

    Article  PubMed  Google Scholar 

  39. Inamoto Y, Chai X, Kurland BF, Cutler C, Flowers ME, Palmer JM, et al. Validation of measurement scales in ocular graft-versus-host disease. Ophthalmology. 2012;119:487–93.

    Article  PubMed  Google Scholar 

  40. Miller KL, Walt JG, Mink DR, Satram-Hoang S, Wilson SE, Perry HD, et al. Minimal clinically important difference for the ocular surface disease index. Arch Ophthalmol. 2010;128:94–101.

    Article  PubMed  Google Scholar 

  41. Ngo W, Situ P, Keir N, Korb D, Blackie C, Simpson T. Psychometric properties and validation of the Standard Patient Evaluation of Eye Dryness questionnaire. Cornea. 2013;32:1204–10.

    Article  PubMed  Google Scholar 

  42. Shimazaki J, Seika D, Saga M, Fukagawa K, Sakata M, Iwasaki M, et al. A prospective, randomized trial of two mucin secretogogues for the treatment of Dry Eye syndrome in office workers. Sci Rep. 2017;7:15210.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Tsubota K, Yokoi N, Shimazaki J, Watanabe H, Dogru M, Yamada M, et al. New perspectives on dry eye definition and diagnosis: a consensus report by the Asia Dry Eye Society. Ocul Surf. 2017;15:65–76.

    Article  PubMed  Google Scholar 

  44. Arita R, Minoura I, Morishige N, Shirakawa R, Fukuoka S, Asai K, et al. Development of definitive and reliable grading scales for meibomian gland dysfunction. Am J Ophthalmol. 2016;169:125–37.

    Article  PubMed  Google Scholar 

  45. Murube J. Characteristics and etiology of conjunctivochalasis: historical perspective. Ocul Surf. 2005;3:7–14.

    Article  PubMed  Google Scholar 

  46. Schirra F, Hoh H, Kienecker C, Ruprecht KW. Using LIPCOF (lid-parallel conjunctival fold) for assessing the degree of dry eye, it is essential to observe the exact position of that specific fold. Adv Exp Med Biol. 1998;438:853–8.

    Article  CAS  PubMed  Google Scholar 

  47. Nemeth J, Fodor E, Lang Z, Kosina-Hagyo K, Berta A, Komar T, et al. Lid-parallel conjunctival folds (LIPCOF) and dry eye: a multicentre study. Br J Ophthalmol. 2012;96:1380–5.

    Article  PubMed  Google Scholar 

  48. 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 

  49. Majhail NS, Rizzo JD, Lee SJ, Aljurf M, Atsuta Y, Bonfim C, et al. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2012;18:348–71.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Finke J, Bethge WA, Schmoor C, Ottinger HD, Stelljes M, Zander AR, et al. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009;10:855–64.

    Article  CAS  PubMed  Google Scholar 

  52. Luznik L, Bolanos-Meade J, Zahurak M, Chen AR, Smith BD, Brodsky R, et al. High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease. Blood. 2010;115:3224–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ogawa Y, Kim SK, Dana R, Clayton J, Jain S, Rosenblatt MI, et al. International chronic ocular graft-vs-host-disease (GVHD) Consensus Group: proposed diagnostic criteria for chronic GVHD (Part I). Sci Rep. 2013;3:3419.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Rapoport Y, Freeman T, Koyama T, Engelhardt BG, Jagasia M, Savani BN, et al. Validation of International Chronic Ocular Graft-Versus-Host Disease (GVHD) Group Diagnostic Criteria as a Chronic Ocular GVHD-Specific Metric. Cornea. 2017;36:258–63.

    Article  PubMed  Google Scholar 

  55. 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 

  56. 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 

  57. Inamoto Y, Martin PJ, Chai X, Jagasia M, Palmer J, Pidala J, et al. Clinical benefit of response in chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2012;18:1517–24.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Greinix HT, Volc-Platzer B, Rabitsch W, Gmeinhart B, Guevara-Pineda C, Kalhs P, et al. Successful use of extracorporeal photochemotherapy in the treatment of severe acute and chronic graft-versus-host disease. Blood. 1998;92:3098–104.

    Article  CAS  PubMed  Google Scholar 

  59. Foss FM, DiVenuti GM, Chin K, Sprague K, Grodman H, Klein A, et al. Prospective study of extracorporeal photopheresis in steroid-refractory or steroid-resistant extensive chronic graft-versus-host disease: analysis of response and survival incorporating prognostic factors. Bone Marrow Transplant. 2005;35:1187–93.

    Article  CAS  PubMed  Google Scholar 

  60. Flowers ME, Apperley JF, van Besien K, Elmaagacli A, Grigg A, Reddy V, et al. A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment of chronic graft-versus-host disease. Blood. 2008;112:2667–74.

    Article  CAS  PubMed  Google Scholar 

  61. Perotti C, Del Fante C, Tinelli C, Viarengo G, Scudeller L, Zecca M, et al. Extracorporeal photochemotherapy in graft-versus-host disease: a longitudinal study on factors influencing the response and survival in pediatric patients. Transfusion. 2010;50:1359–69.

    Article  PubMed  Google Scholar 

  62. 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 

  63. 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 

  64. Couriel DR, Saliba R, Escalon MP, Hsu Y, Ghosh S, Ippoliti C, et al. Sirolimus in combination with tacrolimus and corticosteroids for the treatment of resistant chronic graft-versus-host disease. Br J Haematol. 2005;130:409–17.

    Article  CAS  PubMed  Google Scholar 

  65. Johnston LJ, Brown J, Shizuru JA, Stockerl-Goldstein KE, Stuart MJ, Blume KG, et al. Rapamycin (sirolimus) for treatment of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2005;11:47–55.

    Article  CAS  PubMed  Google Scholar 

  66. Busca A, Saroglia EM, Lanino E, Manfredini L, Uderzo C, Nicolini B, et al. Mycophenolate mofetil (MMF) as therapy for refractory chronic GVHD (cGVHD) in children receiving bone marrow transplantation. Bone Marrow Transplant. 2000;25:1067–71.

    Article  CAS  PubMed  Google Scholar 

  67. Busca A, Locatelli F, Marmont F, Audisio E, Falda M. Response to mycophenolate mofetil therapy in refractory chronic graft-versus-host disease. Haematologica. 2003;88:837–9.

    PubMed  Google Scholar 

  68. Takami A, Mochizuki K, Okumura H, Ito S, Suga Y, Yamazaki H, et al. Mycophenolate mofetil is effective and well tolerated in the treatment of refractory acute and chronic graft-versus-host disease. Int J Hematol. 2006;83:80–85.

    Article  CAS  PubMed  Google Scholar 

  69. Shimmura S, Ono M, Shinozaki K, Toda I, Takamura E, Mashima Y, et al. Sodium hyaluronate eyedrops in the treatment of dry eyes. Br J Ophthalmol. 1995;79:1007–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Yamane M, Ogawa Y, Fukui M, Kamoi M, Uchino M, Saijo-Ban Y, et al. Long-term topical diquafosol tetrasodium treatment of dry eye disease caused by chronic graft-versus-host disease: a retrospective study. Eye Contact Lens. 2018;44 suppl 2:S215-20.

    Article  Google Scholar 

  71. Deinema LA, Vingrys AJ, Wong CY, Jackson DC, Chinnery HR, Downie LE. A randomized, double-masked, placebo-controlled clinical trial of two forms of omega-3 supplements for treating dry eye disease. Ophthalmology. 2017;124:43–52.

    Article  PubMed  Google Scholar 

  72. Dry Eye A, Management Study Research G, Asbell PA, Maguire MG, Pistilli M, Ying GS. et al. n-3 fatty acid supplementation for the treatment of dry eye disease. N Engl J Med. 2018;378:1681–90.

    Article  Google Scholar 

  73. Matsumoto Y, Dogru M, Goto E, Ohashi Y, Kojima T, Ishida R, et al. Autologous serum application in the treatment of neurotrophic keratopathy. Ophthalmology. 2004;111:1115–20.

    Article  PubMed  Google Scholar 

  74. Ogawa Y, Okamoto S, Mori T, Yamada M, Mashima Y, Watanabe R, et al. Autologous serum eye drops for the treatment of severe dry eye in patients with chronic graft-versus-host disease. Bone Marrow Transplant. 2003;31:579–83.

    Article  CAS  PubMed  Google Scholar 

  75. Leite SC, de Castro RS, Alves M, Cunha DA, Correa ME, da Silveira LA, et al. Risk factors and characteristics of ocular complications, and efficacy of autologous serum tears after haematopoietic progenitor cell transplantation. Bone Marrow Transplant. 2006;38:223–7.

    Article  CAS  PubMed  Google Scholar 

  76. Rocha EM, Pelegrino FS, de Paiva CS, Vigorito AC, de Souza CA. GVHD dry eyes treated with autologous serum tears. Bone Marrow Transplant. 2000;25:1101–3.

    Article  CAS  PubMed  Google Scholar 

  77. Zallio F, Mazzucco L, Monaco F, Astori MR, Passera R, Drago G, et al. A single-center pilot prospective study of topical application of platelet-derived eye drops for patients with ocular chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2016;22:1664–70.

    Article  CAS  PubMed  Google Scholar 

  78. Sabti S, Halter JP, Braun Frankl BC, Goldblum D. Punctal occlusion is safe and efficient for the treatment of keratoconjunctivitis sicca in patients with ocular GvHD. Bone Marrow Transplant. 2012;47:981–4.

    Article  CAS  PubMed  Google Scholar 

  79. Geerling G, Tost FH. Surgical occlusion of the lacrimal drainage system. Dev Ophthalmol. 2008;41:213–29.

    Article  PubMed  Google Scholar 

  80. Jacobs DS, Rosenthal P. Boston scleral lens prosthetic device for treatment of severe dry eye in chronic graft-versus-host disease. Cornea. 2007;26:1195–9.

    Article  PubMed  Google Scholar 

  81. Takahide K, Parker PM, Wu M, Hwang WY, Carpenter PA, Moravec C, et al. Use of fluid-ventilated, gas-permeable scleral lens for management of severe keratoconjunctivitis sicca secondary to chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2007;13:1016–21.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Inamoto Y, Sun YC, Flowers ME, Carpenter PA, Martin PJ, Li P, et al. Bandage soft contact lenses for ocular graft-versus-host disease. Biol Blood Marrow Transplant. 2015;21:2002–7.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Magro L, Gauthier J, Richet M, Robin M, Nguyen S, Suarez F, et al. Scleral lenses for severe chronic GvHD-related keratoconjunctivitis sicca: a retrospective study by the SFGM-TC. Bone Marrow Transplant. 2017;52:878–82.

    Article  CAS  PubMed  Google Scholar 

  84. Korb DR, Blackie CA. Using goggles to increase periocular humidity and reduce dry eye symptoms. Eye Contact Lens. 2013;39:273–6.

    Article  PubMed  Google Scholar 

  85. Olson MC, Korb DR, Greiner JV. Increase in tear film lipid layer thickness following treatment with warm compresses in patients with meibomian gland dysfunction. Eye Contact Lens. 2003;29:96–99.

    Article  PubMed  Google Scholar 

  86. Perry HD, Doshi-Carnevale S, Donnenfeld ED, Solomon R, Biser SA, Bloom AH. Efficacy of commercially available topical cyclosporine A 0.05% in the treatment of meibomian gland dysfunction. Cornea. 2006;25:171–5.

    Article  PubMed  Google Scholar 

  87. Frucht-Pery J, Sagi E, Hemo I, Ever-Hadani P. Efficacy of doxycycline and tetracycline in ocular rosacea. Am J Ophthalmol. 1993;116:88–92.

    Article  CAS  PubMed  Google Scholar 

  88. Sall K, Stevenson OD, Mundorf TK, Reis BL. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 3 Study Group. Ophthalmology. 2000;107:631–9.

    Article  CAS  PubMed  Google Scholar 

  89. Wang Y, Ogawa Y, Dogru M, Kawai M, Tatematsu Y, Uchino M, et al. Ocular surface and tear functions after topical cyclosporine treatment in dry eye patients with chronic graft-versus-host disease. Bone Marrow Transplant. 2008;41:293–302.

    Article  CAS  PubMed  Google Scholar 

  90. Robinson MR, Lee SS, Rubin BI, Wayne AS, Pavletic SZ, Bishop MR, et al. Topical corticosteroid therapy for cicatricial conjunctivitis associated with chronic graft-versus-host disease. Bone Marrow Transplant. 2004;33:1031–5.

    Article  CAS  PubMed  Google Scholar 

  91. Abud TB, Amparo F, Saboo US, Di Zazzo A, Dohlman TH, Ciolino JB, et al. A Clinical Trial Comparing the Safety and Efficacy of Topical Tacrolimus versus Methylprednisolone in Ocular Graft-versus-Host Disease. Ophthalmology. 2016;123:1449–57.

    Article  PubMed  Google Scholar 

  92. Jung JW, Lee YJ, Yoon SC, Kim TI, Kim EK, Seo KY. Long-term result of maintenance treatment with tacrolimus ointment in chronic ocular graft-versus-host disease. Am J Ophthalmol. 2015;159:519–27 e511.

    Article  CAS  PubMed  Google Scholar 

  93. Kheirkhah A, Di Zazzo A, Satitpitakul V, Fernandez M, Magilavy D, Dana R. A pilot randomized trial on safety and efficacy of a novel topical combined inhibitor of janus kinase 1/3 and spleen tyrosine kinase for GVHD-associated ocular surface disease. Cornea. 2017;36:799–804.

    Article  PubMed  Google Scholar 

  94. Ogawa Y, Dogru M, Uchino M, Tatematsu Y, Kamoi M, Yamamoto Y, et al. Topical tranilast for treatment of the early stage of mild dry eye associated with chronic GVHD. Bone Marrow Transplant. 2010;45:565–9.

    Article  CAS  PubMed  Google Scholar 

  95. Amparo F, Dastjerdi MH, Okanobo A, Ferrari G, Smaga L, Hamrah P, et al. Topical interleukin 1 receptor antagonist for treatment of dry eye disease: a randomized clinical trial. JAMA Ophthalmol. 2013;131:715–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Holland EJ, Luchs J, Karpecki PM, Nichols KK, Jackson MA, Sall K, et al. Lifitegrast for the treatment of dry eye disease: results of a phase iii, randomized, double-masked, placebo-controlled trial (OPUS-3). Ophthalmology. 2017;124:53–60.

    Article  PubMed  Google Scholar 

  97. Peris-Martinez C, Menezo JL, Diaz-Llopis M, Avino-Martinez JA, Navea-Tejerina A, Risueno-Reguillo P. Multilayer amniotic membrane transplantation in severe ocular graft-versus host disease. Eur J Ophthalmol. 2001;11:183–6.

    Article  CAS  PubMed  Google Scholar 

  98. Yeh PT, Hou YC, Lin WC, Wang IJ, Hu FR. Recurrent corneal perforation and acute calcareous corneal degeneration in chronic graft-versus-host disease. J Formos Med Assoc. 2006;105:334–9.

    Article  PubMed  Google Scholar 

  99. Meller D, Fuchsluger T, Pauklin M, Steuhl KP. Ocular surface reconstruction in graft-versus-host disease with HLA-identical living-related allogeneic cultivated limbal epithelium after hematopoietic stem cell transplantation from the same donor. Cornea. 2009;28:233–6.

    Article  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

CIBMTR Support List, The CIBMTR is supported primarily by the Public Health Service Grant/Cooperative Agreement 5U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 4U10HL069294 from NHLBI and NCI; a contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); two Grants N00014-17-1-2388 and N0014-17-1-2850 from the Office of Naval Research; and grants from *Actinium Pharmaceuticals, Inc.; *Amgen, Inc.; *Amneal Biosciences; *Angiocrine Bioscience, Inc.; Anonymous donation to the Medical College of Wisconsin; Astellas Pharma US; Atara Biotherapeutics, Inc.; Be the Match Foundation; *bluebird bio, Inc.; *Bristol Myers Squibb Oncology; *Celgene Corporation; Cerus Corporation; *Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Gamida Cell Ltd.; Gilead Sciences, Inc.; HistoGenetics, Inc.; Immucor; *Incyte Corporation; Janssen Scientific Affairs, LLC; *Jazz Pharmaceuticals, Inc.; Juno Therapeutics; Karyopharm Therapeutics, Inc.; Kite Pharma, Inc.; Medac, GmbH; MedImmune; The Medical College of Wisconsin; *Mediware; *Merck & Co, Inc.; *Mesoblast; MesoScale Diagnostics, Inc.; Millennium, the Takeda Oncology Co.; *Miltenyi Biotec, Inc.; National Marrow Donor Program; *Neovii Biotech NA, Inc.; Novartis Pharmaceuticals Corporation; Otsuka Pharmaceutical Co, Ltd. – Japan; PCORI; *Pfizer, Inc; *Pharmacyclics, LLC; PIRCHE AG; *Sanofi Genzyme; *Seattle Genetics; Shire; Spectrum Pharmaceuticals, Inc.; St. Baldrick’s Foundation; *Sunesis Pharmaceuticals, Inc.; Swedish Orphan Biovitrum, Inc.; Takeda Oncology; Telomere Diagnostics, Inc.; and University of Minnesota. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration (HRSA) or any other agency of the U.S. Government. *Corporate Members

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yoshihiro Inamoto.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Inamoto, Y., Valdés-Sanz, N., Ogawa, Y. et al. Ocular graft-versus-host disease after hematopoietic cell transplantation: Expert review from the Late Effects and Quality of Life Working Committee of the CIBMTR and Transplant Complications Working Party of the EBMT. Bone Marrow Transplant 54, 662–673 (2019). https://doi.org/10.1038/s41409-018-0340-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-018-0340-0

This article is cited by

Search

Quick links