Ocular Graft Versus Host Disease

Maarij Mirza

Introduction

Graft-versus-host disease (GvHD) can occur following solid organ transplants or haematopoietic stem cell transplantation (HSCT) in patients with blood disorders, malignancies, immunodeficiencies or inherited metabolic diseases (1). Approximately 40-60% of recipients receiving allogenic HSCT from donors develop GvHD (2). It is a T-cell mediated process from the recipient due to tissue antigen mismatches between major or minor histocompatibility antigens (3). This complication can be acute or chronic in onset, affecting multiple organs and body systems including the eyes – also known as ocular graft-versus-host disease.

Epidemiology

Ocular GvHD can present acutely within three months or as a chronic complication taking years to develop following transplant and is often the first presentation of systemic GvHD. It’s incidence varies across literature, with studies citing 40-90% of patients with allogenic HSCT from human leukocyte antigen-matched donors developing GvHD (4). The immune response leads to infiltration and inflammation of ocular surfaces, ultimately causing fibrosis, scarring and a reduction in conjunctival goblet cells. Risk factors for the development of ocular GvHD include older age, female sex, Asian or African American ethnicities, diabetes mellitus, EBV-positive donors and preceding skin, liver or mouth manifestations of the disease (5-7).

Presentation and Diagnosis

The most common ocular manifestation of GvHD is keratoconjunctivitis sicca, however, it can affect any ocular surface in the anterior segment of the eye and even the lacrimal system. The disease process is multi-factorial as fibrosis of ocular surfaces leads to reduced secretions and can be compounded by the immunosuppressive therapies and toxicity of radiotherapy and chemotherapy regimens patients may be subject to (2). Patients can present with disturbed vision, dry eye syndrome (DES) and light sensitivity. Evidence of conjunctival hyperaemia, meibomian gland dysfunction, punctate epithelial erosions and subconjunctival fibrosis may also be present. Complications such as cataracts, corneal ulcerations and even perforation can occur in severe cases (6,8).

Diagnostic criteria and grading systems have been proposed for ocular GvHD but there is no consensus at present on an international scale. The National Institutes of Health Consensus (NIH) and International Chronic Ocular GvHD Consensus Group (ICOGCG) criteria are most commonly used amongst literature (9,10). Subjective symptoms of ocular discomfort can be scored by recording the number of times patient use lubricating drops as seen in NIH criteria, or by utilising the Ocular Surface Disease Index (OSDI) validated questionnaire as done for ICOGCG criteria (11). Objective parameters involving the assessment of the ocular surface can be conducted through the Schirmer test, tear film break-up time (TBUT) and corneal fluorescein staining.

Management and Prognosis

For mild symptoms of dry eye, patients can be managed with preservative free lubricants that can be sought over the counter. Punctal plugging of lacrimal ducts can also play a role in supporting the maintenance of the tear film by reducing drainage.

Topical immunosuppression through corticosteroid use, tacrolimus and ciclosporin are commonly used agents for the management as well as prevention of ocular GvHD which has been well tolerated by patients. The use of these medicated drops should be closely monitored and long-term use discouraged due to adverse effects (12). Topical antibiotic use may also be considered for treatment or prophylaxis where epithelial defects or corneal melting is evident.

Moderate to severe cases are typically managed with liaison between ophthalmology and haematology if the case necessitates systemic therapy and does not respond to topical strategies alone. This involves high dose steroid regimens which can be given alongside calcineurin inhibitors and disease modifying anti-rheumatic drugs (DMARDs).

In the last year, belumosudil (inhibitor of Rho-associated coiled-coil kinase 2) has been licensed within the United Kingdom for the treatment of chronic GvHD in steroid-refractory cases (13). Despite its relative success for systemic GvHD (42% overall response rate from the ROCKstar trial), it is yet to be evaluated for ocular GvHD specifically (14). Ruxolitinib is a type of targeted cancer drug which has also shown promise for systemic GvHD but is not currently available through the National Health Service.

Procedures can also be offered to specific cases of ocular GvHD. Punctal cauterisation can be used in cases where punctal plugging has not been well tolerated to maintain an adequate tear film (15). Tarsorrhaphy involves partial or complete closure of the eye lids on a temporary basis to protect the cornea and prevent corneal damage in instances where systemic therapies have been newly commenced (16).  Amniotic membrane transplantation (AMT) can reconstruct the ocular surface in patients with ocular GvHD by protecting the cornea and promoting epithelialisation in persistent cases with corneal ulceration (17). Corneal perforation is a rare but major complication of ocular GvHD and may require keratoplasty where patients receive a full thickness graft cornea (18). 

References

1.         Hamilton BK. Updates in chronic graft-versus-host disease. Hematology. 2021 Dec 10;2021(1):648–54.

2.         Munir SZ, Aylward J. A Review of Ocular Graft-Versus-Host Disease. Optometry and Vision Science. 2017 May;94(5):545.

3.         Choi SW, Levine JE, Ferrara JLM. Pathogenesis and management of graft-versus-host disease. Immunol Allergy Clin North Am. 2010 Feb;30(1):75–101.

4.         Townley JR, Dana R, Jacobs DS. Keratoconjunctivitis Sicca Manifestations in Ocular Graft Versus Host Disease: Pathogenesis, Presentation, Prevention, and Treatment. Seminars in Ophthalmology. 2011 Sep 1;26(4–5):251–60.

5.         Wang JCC, 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. British Journal of Ophthalmology. 2015 Nov;99(11):1514.

6.         Pellegrini M, Bernabei F, Barbato F, Arpinati M, Giannaccare G, Versura P & Bonifazi F. Incidence, Risk Factors and Complications of Ocular Graft-Versus-Host Disease Following Hematopoietic Stem Cell Transplantation. American Journal of Ophthalmology. 2021 Jul 1;227:25–34.

7.         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 Nov;50(11):1459–64.

8.         Bourdin A, Gournay V, Doan S, Prata P H, Kaphan E, Michonneau D, Socie G, Peffault de Latour R & Gabison E E. Severe corneal manifestations of graft-versus-host disease: Experience of a tertiary referral center. The Ocular Surface. 2025 Apr 1;36:19–24.

9.         Ogawa Y, Kim SK, Dana R, Clayton J, Jain S, Rosenblatt MI, Perez V L, Shikari H, Riemens A & Tsubota K. International Chronic Ocular Graft-vs-Host-Disease (GVHD) Consensus Group: proposed diagnostic criteria for chronic GVHD (Part I). Sci Rep. 2013 Dec 5;3:3419.

10. 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 Mar;21(3):389-401.e1.

11. Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and Validity of the Ocular Surface Disease Index. Archives of Ophthalmology. 2000 May 1;118(5):615–21.

12. X L, Hd C. Ocular manifestations of graft-versus-host disease: 10 years’ experience. Clinical ophthalmology (Auckland, NZ) [Internet]. 2015 Mar 7 [cited 2025 Jan 17];9. Available from: https://pubmed.ncbi.nlm.nih.gov/26170614/

13. Overview | Belumosudil for treating chronic graft-versus-host disease after 2 or more systemic treatments in people 12 years and over | Guidance | NICE [Internet]. NICE; 2024. Available from: https://www.nice.org.uk/guidance/ta949

14. 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 Dec 2;138(22):2278–89.

15. Yaguchi S, Ogawa Y, Kamoi M, Uchino M, Tatematsu Y, Ban Y, Ohba E, Okamoto S, Goto E & Tsubota K. Surgical management of lacrimal punctal cauterization in chronic GVHD-related dry eye with recurrent punctal plug extrusion. Bone Marrow Transplant. 2012 Nov;47(11):1465–9.

16. Tung CI. Current Approaches to Treatment of Ocular Graft-Versus-Host Disease. International Ophthalmology Clinics. 2017 Spring;57(2):65.

17. Schuerch K, Baeriswyl A, Frueh BE & Tappeiner C. Efficacy of Amniotic Membrane Transplantation for the Treatment of Corneal Ulcers. Cornea. 2020 Apr;39(4):479–83.

18. Sinha S, Singh RB, Dohlman TH, Taketani Y, Yin J & Dana R. Prevalence and Risk Factors Associated With Corneal Perforation in Chronic Ocular Graft-Versus-Host-Disease. Cornea. 2021 Jul 1;40(7):877–82.

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