Current Approaches to Treatment of Ocular Graft-Versus-Host Disease

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In the past few decades, allogeneic hematopoietic stem cell transplantation (allo-HSCT) has become successful in treating a variety of hematologic disorders, both benign and malignant, including leukemia, lymphoma, multiple myeloma, aplastic anemia, sickle cell disease, among others.1,2 Graft-versus-host disease (GVHD) has emerged as an important and highly morbid complication of allo-HSCT, limiting the success of allo-HSCT. It is a multifactorial, immune-mediated disease involving a complex interaction between donor and recipient cells, particularly involving CD4+ and CD8+ T cells.1 Incidence of GVHD in post-allo-HSCT patients has been reported to be from 10% to 90%.3 Overall mortality after allo-HSCT, including causes unrelated to GVHD, has been reported to be about 40%.4
GVHD manifests in the skin, liver, lung, gastrointestinal tract, mouth, eye, and other mucous membranes.5 Of patients receiving allo-HSCT, 40% to 60% go on to develop GVHD of the eye. Ocular GVHD is primarily a condition involving lacrimal gland dysfunction, meibomian gland dysfunction, conjunctival inflammation, and cicatricial scarring.5–8 Involvement of other structures of the eye has been reported, from uveitis to choroiditis, to ischemic disease, but it is unclear whether these are the results of GVHD or other underlying conditions.6,9–11 Risk factors for ocular GVHD include female donor to male recipient allo-HSCT, older recipient age, peripheral blood stem cell transplant, skin and mouth involvement, lack of prophylaxis for acute GVHD, and prior acute GVHD.12
Acute systemic GVHD is an exaggerated inflammatory response of donor lymphocytes to their foreign host cells that are already damaged by the pre-allo-HSCT conditioning regimen or by the cancer itself. The result is a “cytokine storm,”13 which can manifest as skin desquamation, severe bile duct injury, and drop out of gastrointestinal crypts.5 In the eye, it can present with pseudomembranous conjunctivitis and corneal epithelial sloughing in severe stages.
Chronic GVHD is a poorly understood condition3 with Sjögren-like features, which may result from loss of normal immune regulation following pre-allo-HSCT conditioning.1 It is characterized by fibrosis, stenosis, and atrophy of the skin, lung, and mucous membranes,14 and in the eye, it presents with keratoconjunctivitis sicca, punctate keratopathy, and cicatricial conjunctivitis.15 Histologically, chronic GVHD of the eye demonstrates extensive fibrosis in the lacrimal gland, increased levels of CD-34+ stromal fibroblasts, and excessive production of extracellular matrix components.16
Recent classification of systemic GVHD has been established by the 2005 National Institutes for Health consensus15 as follows: (1) classic acute GVHD with typical acute GVHD features occurring within 100 days after allo-HSCT; (2) persistent, recurrent, or late acute GVHD occurring after 100 days; (3) classic chronic GVHD without features of acute GVHD; and (4) overlap syndrome that exhibits features or both acute and chronic GVHD.
Perhaps the closest attempt to classify features of acute ocular GVHD is the conjunctival grading system created by Jabs et al.17 Attempts have been made to classify chronic ocular GVHD, and historical classification schemes have been imperfect.15,17,18 In many cases, it can be difficult to diagnose whether a patient has chronic ocular GVHD or simply dry eye post-allo-HSCT. Recently, the International Consensus Group on Chronic Ocular GVHD19 proposed a system using 4 criteria (symptom score measured by the Ocular Surface Disease Index, tear production measured by Schirmer I test, corneal epitheliopathy based on corneal fluorescein staining, and severity of conjunctival injection) to establish definite, probable, or absence of chronic ocular GVHD.
Ultimately, close communication between the stem cell transplant physician and the ophthalmologist becomes critical for successful diagnosis and treatment of ocular GVHD. This review will focus on treatment of ocular GVHD.

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