Ocular graft-versus-host disease (oGVHD) is an ocular manifestation of graft-versus-host disease (GVHD) that occurs after allogeneic hematopoietic stem cell transplantation (AHSCT). GVHD is an excessive systemic inflammatory reaction in which donor-derived T cells attack the host’s normal tissues, affecting organs such as the skin, liver, gastrointestinal tract, lungs, and eyes.
oGVHD develops in 40–60% of HSCT patients 1). A meta-analysis of 17 studies involving 4,501 patients reported a pooled prevalence of oGVHD of 37.8%, with 46.7% by NIH criteria and 33.7% by ICCGVHD criteria 4). Among patients with chronic GVHD, 40–90% develop ocular symptoms. Dry eye is observed in about 50% of patients at 6 months post-transplant, and many cases progress rapidly to severe dry eye findings. Acute oGVHD occurs in approximately 7.2% of allo-HSCT patients 7).
GVHD was traditionally classified as acute if occurring within 100 days post-transplant and chronic if after 100 days. Currently, classification is based on specific tissue involvement rather than onset time. Acute GVHD affects the skin, oral mucosa, gastrointestinal mucosa, lungs, and liver. Chronic GVHD additionally more frequently involves the eyes, musculoskeletal system, lymphohematopoietic system, and genitalia.
Acute oGVHD primarily involves the cornea and conjunctiva, with pseudomembranous conjunctivitis and macular erythema being characteristic 1). Chronic oGVHD presents with more extensive and persistent damage, including severe dry eye due to fibrosis of the lacrimal and meibomian glands, conjunctival scarring, and corneal ulcers. Chronic oGVHD is associated with long-term tissue fibrosis and has a poorer prognosis 1).
Keratoconjunctivitis sicca (KCS) is observed in 69–77% of oGVHD cases and is the most characteristic finding 1). T-cell infiltration around the lacrimal gland ducts leads to inflammation and fibrotic reactions that destroy the glandular secretory units 1).
Acute oGVHD
Pseudomembranous conjunctivitis: Formation of pseudomembrane on the palpebral conjunctiva 5)
Hemorrhagic conjunctivitis: Conjunctival hyperemia with serosanguinous exudate 5)
Corneal epithelial detachment: Observed in severe cases 5)
Eyelid swelling: Accompanied by increased discharge 7)
Chronic oGVHD
Meibomian gland dysfunction (MGD): Prevalence reaches 47.8–68.4% 5). Accompanied by thickening and keratinization of the eyelid margin.
Superficial punctate keratopathy (SPK) and filamentary keratitis: In advanced cases, may lead to corneal ulceration and perforation 5)
Conjunctival hyperemia and pseudomembrane formation: Observed in the acute phase.
Conjunctival scarring and symblepharon: Subconjunctival fibrosis is observed in approximately 50% of cases 6)
Tear and Adnexal Findings
Decreased tear secretion: Evaluated by Schirmer test. Due to scarring of the lacrimal gland.
Increased tear osmolarity: A worsening factor for ocular surface inflammation.
Punctal fibrosis: Obstruction of tear drainage pathway.
Eyelid telangiectasia: A finding reflecting chronic inflammation.
Decreased conjunctival goblet cell density: Accompanied by conjunctival squamous metaplasia. Thinning of the mucin layer occurs6).
T cell-mediated damage to meibomian gland epithelial cells and hyperkeratinization of the ductal epithelium are the main causes of obstructive MGD6). Although aqueous-deficient dry eye due to lacrimal gland dysfunction is predominant, evaporative dry eye due to MGD also coexists, presenting as mixed-type dry eye5). Pretreatment chemotherapy and radiotherapy may destroy normal quiescent progenitor cells of the meibomian gland, impairing cell replacement capacity after holocrine secretion8).
Because large amounts of immunosuppressive drugs are used, infections are more likely to occur, and corneal ulcers may develop and lead to perforation. KCS can persist for several years even after other systemic symptoms of cGVHD have resolved.
Dry eye due to GVHD results from immunological destruction of the lacrimal gland, and its symptoms and treatment are similar to Sjögren’s syndrome. However, the pathogenesis differs. Sjögren’s syndrome is caused by autoimmune chronic lymphocytic infiltration of the lacrimal and salivary glands. oGVHD is fundamentally different in that donor-derived alloreactive T cells attack the lacrimal gland.
The root cause of oGVHD is the attack of host tissues by donor-derived T cells following allogeneic hematopoietic stem cell transplantation. Thymic damage from conditioning or acute GVHD leads to breakdown of central immune tolerance, resulting in abnormal proliferation of autoreactive T cells (mainly CD4+ Th2) and B cells, and autoantibody formation.
Meta-analysis has identified the following risk factors and odds ratios4).
| Risk Factor | OR (95% CI) |
|---|---|
| Advanced age | 1.10 (1.00-1.20) |
| Female donor | 1.48 (1.20-1.83) |
| Related donor (MRD) | 1.50 (1.22-1.83) |
| Peripheral blood stem cells (PBSC) | 1.81 (1.38-2.39) |
| History of acute GVHD | 1.74 (1.29-2.35) |
| Chronic GVHD | 3.04 (1.82-5.08) |
| Skin GVHD | 5.55 (2.41-12.79) |
| Oral GVHD | 13.83 (5.09-37.56) |
The odds ratios for oral GVHD and skin GVHD are particularly high, and ophthalmologic evaluation should be initiated early in patients with these organ GVHDs 4). Skin acute GVHD of grade II or higher is an important risk factor for the development of conjunctival acute GVHD 7).
All cases have a history of allogeneic bone marrow transplantation. In addition to a complete ophthalmic examination, the following evaluations are performed.
Several criteria have been proposed for the diagnosis of oGVHD. Pre-transplant ocular surface evaluation (baseline) is important for accurately determining new onset after transplantation 5).
| Criteria | Main Components | Features |
|---|---|---|
| NIH CC (2014) | Schirmer ≤5mm + KCS | Most widely used. The 2014 revision excluded Schirmer values from severity grading. |
| ICCGVHD | OSDI + Schirmer + CFS + conjunctival hyperemia | Combination of objective indicators |
| TFOS DEWS II expanded | OSDI ≥13 + TBUT/osmolarity/staining | Includes evaporative dry eye by incorporating TBUT |
The ICCGVHD criteria assign severity scores of 0 to 3 to four parameters: OSDI, Schirmer test, corneal fluorescein staining, and conjunctival hyperemia. The total score and the presence or absence of systemic cGVHD determine the diagnosis of oGVHD.
| Score | OSDI | Schirmer test (mm) | Corneal staining |
|---|---|---|---|
| 0 | <13 | >15 | None |
| 1 | 13–22 | 11–15 | Mild |
| 2 | 23–32 | 6–10 | Moderate |
| 3 | ≥33 | ≤5 | Severe |
Total score 0–4: none, 5–8: mild to moderate, 9–11: severe2). If systemic GVHD is positive, a score of 6 or higher is diagnosed as definite oGVHD5).
According to NIH criteria, Schirmer test ≤5 mm/5 min or Schirmer ≤10 mm/5 min due to other causes, plus confirmation of KCS by slit-lamp examination5). Ocular symptoms alone are insufficient for a definitive diagnosis of cGVHD; evidence from other organs is required.
Cytokine profiling in tears is the most studied biomarker for oGVHD2). According to a systematic review of 19 studies, tear levels of ICAM-1, IL-6, and IL-8 are higher in oGVHD patients than in dry eye patients and may serve as signals of disease severity2). Mucous membrane pemphigoid-9 expression is also elevated in oGVHD patients2). Tear lipid profiles (phosphatidylcholine, sphingomyelin, lactosylceramide) also show strong correlation with NIH eye score and TBUT2).
A predictive model combining IL-8/CXCL8 and IP-10/CXCL10 achieves sensitivity of 86.4% and specificity of 95.2%6). Pre-transplant tear concentrations of fractalkine, IL-1Ra, and IL-6 may serve as markers predicting oGVHD onset6). Tear proteomic analysis has identified 79 proteins differentially expressed in oGVHD, with histone proteins being the most highly upregulated6).
In a systematic review by Bohlen et al., a wide range of biomarkers including tear cytokines, proteome, lipids, leukocytes, and ocular surface microbiota were examined, and cytokine profiling was concluded to be the most promising2).
The ICOCG composite scoring is standard. Each of the four items—OSDI (subjective symptom score), Schirmer test without anesthesia, corneal fluorescein staining, and conjunctival hyperemia—is scored from 0 to 3, and the total score (maximum 11) determines severity: 0–4 none, 5–8 mild to moderate, 9–11 severe2). This scoring was validated in a 2017 study.
The NIH consensus guidelines set four treatment goals: (1) lubrication, (2) suppression of tear evaporation, (3) control of tear drainage, and (4) reduction of ocular surface inflammation6).
Starting 0.5% cyclosporine eye drops one month before bone marrow transplantation is recommended for prevention of oGVHD, but this has not been verified in large-scale randomized controlled trials.
If conservative treatment does not improve the condition, consider the following:
Mesenchymal stem cells (MSCs) have immunosuppressive and tissue regenerative properties and are being studied as a novel treatment for oGVHD1)3). MSCs produce immunomodulatory factors such as IL-10, TGF-β, IDO, and PGE2, and suppress the activation of T cells and NK cells3). Differentiation into corneal epithelial cells and regeneration of lacrimal and meibomian glands have also been experimentally demonstrated1)3). MSC-derived exosomes (MSC-Exo) are safe as a cell-free therapy and are expected to be applied in eye drops1)3). However, further large-scale clinical trials are needed for clinical application.
The central mechanism of tear secretion impairment in oGVHD is immunological destruction of the lacrimal gland. Donor-derived CD4+ and CD8+ T cells infiltrate the periductal area of the lacrimal gland, triggering inflammation and fibrosis1)6). Fibroblasts highly expressing HSP47 are activated and synthesize excessive collagen, leading to lacrimal gland fibrosis6). Approximately 50% of lacrimal gland fibroblasts are donor-derived and contribute to the pathology of GVHD together with T cells and recipient-derived fibroblasts5). Epithelial-mesenchymal transition (EMT) is also an important mechanism of lacrimal gland fibrosis9).
Damage to Lacrimal and Meibomian Glands
Periductal T cell infiltration: The periductal area of the lacrimal gland is the main target site1).
Destruction of glandular secretory units: Fibrosis progresses and tear secretion capacity is lost.
Meibomian gland obstruction: T cell-mediated MG epithelial cell damage and ductal epithelial hyperkeratinization are the main causes of obstructive MGD6).
Oxidative stress: Accumulation of lipofuscin-like inclusions causes oxidative damage to lacrimal acinar cells, reducing tear production6).
Damage to Cornea and Conjunctiva
Corneal epithelial damage: Progresses stepwise from punctate keratitis to filamentary keratitis, persistent epithelial defects, corneal ulcers, and perforation6).
Decreased corneal endothelial cell density: Already lower than healthy individuals before HSCT, and further decreases with the onset of oGVHD. Increased NK1R expression is involved6).
Corneal neuropathy: Activation of the abnormal complement C3/CD4+ T cell axis leads to neurotrophic ulcers6).
Conjunctival fibrosis: NETs (neutrophil extracellular traps) released from neutrophils promote proliferation and differentiation of conjunctival fibroblasts6).
Donor-derived alloreactive T lymphocytes play a crucial role in the pathogenesis of GVHD. Thymic damage caused by conditioning regimens and acute GVHD leads to breakdown of central immune tolerance, resulting in abnormal proliferation of autoreactive T cells (mainly CD4+ Th2) and B cells, as well as autoantibody formation. Both cellular and humoral immunity are involved in oGVHD.
Activation of the cytokine cascade plays an important role. Preventing T cell activation and proliferation is the focus of GVHD treatment and prevention, and cyclosporine, tacrolimus, and monoclonal antibodies are used 1).
MSCs produce the following immunomodulatory factors and suppress various immune cells involved in the pathogenesis of oGVHD 3).
MSCs express apoptosis-inducing molecules such as PDL-1, PDL-2, and FasL, and induce caspase-3-dependent apoptosis of activated T cells and NK cells 3).
Ye et al. reviewed the therapeutic effects of MSCs and MSC-derived exosomes (MSC-Exo) on oGVHD 1). MSCs have the ability to differentiate into corneal epithelial cells and improve corneal damage through secretion of anti-inflammatory proteins such as TSG-6 1). Subconjunctivally injected human MSCs protect the cornea from T cell invasion in oGVHD and also show effects on the contralateral eye 1). MSC injection improved Schirmer values in 54.55% of cases 6).
Harrell et al. showed that MSCs produce immunomodulatory factors such as IL-10, TGF-β, IDO, NO, and PGE2, altering the phenotype and function of all immune cells involved in the pathogenesis of oGVHD 3).
MSC-Exo, due to their lipid membrane and nano-size, can penetrate biological barriers in the eye and deliver cargo directly to damaged corneal epithelial cells and infiltrating leukocytes 3). In a prospective clinical trial, MSC-Exo were administered to 28 eyes with refractory oGVHD-related dry eye, resulting in decreased fluorescein scores, prolonged TBUT, increased tear secretion, and reduced OSDI scores 6). Amniotic fluid-derived MSC-Exo (AF-MSC-Exo) are rich in NGF and BDNF, which may contribute to retinal regeneration via neurotrophic factors 3). As a cell-free therapy, it has excellent safety and lower risk of side effects from long-term use compared to MSC transplantation 3).
Combination of regulatory T cells (Tregs) and BETi has been reported to increase Treg numbers and significantly improve GVHD clinical scores 6).
However, further large-scale clinical trials are needed for clinical application of MSC-Exo, and establishing optimal dose, administration frequency, and long-term safety remain challenges 1).
Bohlen et al. systematically reviewed 19 studies published between 2018 and 2023, comprehensively evaluating molecular biomarkers for oGVHD 2). Tear cytokines, proteome, lipid profile, leukocytes, and microbiota were examined, with cytokine profiling being the most studied biomarker 2).
Elevations of ICAM-1, IL-6, and IL-8 may reflect disease severity, while decreases in EGF and IL-7 could serve as useful biomarkers for differentiating oGVHD from dry eye 2).
Tear lipid profiles (phosphatidylcholine, sphingomyelin, lactosylceramide) also show strong correlations with clinical parameters and are promising biomarker candidates 2). A decrease in ocular surface microbiota diversity has also been observed after HSCT, suggesting an association with the development of oGVHD 2).
