Ocular graft-versus-host disease (oGVHD) is an ocular manifestation of graft-versus-host disease (GVHD) that develops 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 occurs in 40–60% of HSCT patients 1). A meta-analysis of 17 studies and 4,501 cases reported a pooled prevalence of oGVHD of 37.8%, with 46.7% by NIH consensus criteria and 33.7% by the International Chronic Ocular GVHD Consensus Group (ICCGVHD) criteria 4). A review reported that 60–90% of chronic GVHD patients have ocular symptoms 5). Dry eye is observed in over 50% of patients around 6–24 months after transplantation and can become severe 9). Acute oGVHD occurs in approximately 7.2% of allo-HSCT patients 7).
GVHD was previously classified as acute if occurring within 100 days after transplantation and chronic if occurring after 100 days. Currently, classification is based on specific tissue pathology rather than onset time. The main target organs of acute GVHD are the skin, gastrointestinal tract, and liver. Chronic GVHD can cause characteristic lesions in a wider range of organs, including the oral cavity, eyes, lungs, fascia, and genitalia 12).
Acute oGVHD primarily involves the cornea and conjunctiva, with characteristic features such as pseudomembranous conjunctivitis and periorbital maculopapular rash 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 involves long-term tissue fibrosis and has a poorer prognosis 1).
Keratoconjunctivitis sicca (KCS) is present in 69–77% of oGVHD cases and is the most characteristic finding 1). T-cell infiltration occurs around the lacrimal gland ducts, and inflammation and fibrotic reactions destroy the glandular secretory units 1).
Acute oGVHD
Pseudomembranous conjunctivitis: Formation of pseudomembrane on the palpebral conjunctiva5)
Hemorrhagic conjunctivitis: Conjunctival hyperemia with serosanguinous exudate5)
Corneal epithelial detachment: Seen in severe cases5)
Eyelid swelling: Accompanied by increased discharge7)
Chronic oGVHD
Meibomian gland dysfunction (MGD): Prevalence reaches 47.8–68.4%5). Accompanied by thickening and keratinization of the eyelid margin.
Superficial punctate keratitis (SPK) and filamentary keratitis: In advanced cases, may progress to corneal ulceration and perforation5)
Conjunctival hyperemia and pseudomembrane formation: Observed in the acute phase.
Conjunctival scarring and symblepharon: Subconjunctival fibrosis is seen in approximately 50% of cases6)
Tear and adnexal findings
Decreased tear secretion: Assessed by Schirmer test. Due to scarring of the lacrimal gland.
Increased tear osmolarity: Becomes an exacerbating factor for ocular surface inflammation.
Lacrimal 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 the predominant type is aqueous-deficient dry eye due to lacrimal gland dysfunction, evaporative dry eye due to MGD also coexists, resulting in a mixed-type dry eye presentation5). Pretreatment chemotherapy and radiotherapy may destroy normal resting progenitor cells of the meibomian glands, impairing the ability to replenish cells after holocrine secretion8).
Because large doses of immunosuppressive drugs are used, infections are more likely to occur, and corneal ulcers may develop and progress 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 is similar in symptoms and treatment 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 donor-derived T cells on host tissues following allogeneic hematopoietic stem cell transplantation. Thymic damage from conditioning regimens or 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.
Meta-analysis has identified the following risk factors and odds ratios4).
| Risk Factor | OR (95% CI) |
|---|---|
| Older 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 ophthalmic evaluation should be initiated early in patients with these organ GVHDs4). Skin acute GVHD of grade II or higher is an important risk factor for the development of conjunctival acute GVHD7).
History of allogeneic hematopoietic stem cell transplantation. In addition to a complete ophthalmic examination, perform the following evaluations.
Several criteria have been proposed for the diagnosis of oGVHD. Pre-transplant ocular surface evaluation (baseline) is important for accurately determining new onset after transplantation5).
| Criteria | Main Components | Features |
|---|---|---|
| NIH CC (2014) | Schirmer ≤5mm + KCS | Most widely used. Schirmer value excluded from severity in 2014 revision |
| ICCGVHD | OSDI + Schirmer + CFS + hyperemia | Combination of objective indicators |
| TFOS DEWS II expanded | OSDI ≥13 + TBUT/osmolarity/staining | Includes evaporative type by incorporating TBUT |
The ICCGVHD criteria assign a severity score of 0 to 3 to four parameters: OSDI, Schirmer test, corneal fluorescein staining, and conjunctival hyperemia. The diagnosis of oGVHD is determined by the total score and the presence or absence of systemic cGVHD.
| 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). In cases with systemic GVHD, a score of 6 or higher is diagnosed as definite oGVHD5).
According to the 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; corroboration 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). Matrix metalloproteinase 9 (MMP-9) expression is also elevated in oGVHD patients2). Tear lipid profiles (phosphatidylcholine, sphingomyelin, lactosylceramide) also show strong correlations with NIH eye score and TBUT2).
A predictive model combining IL-8/CXCL8 and IP-10/CXCL10 achieves a 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), unanesthetized Schirmer test, corneal fluorescein staining, and conjunctival hyperemia—is scored from 0 to 3, and the total score (maximum 11 points) determines severity. A score of 0–4 indicates none, 5–8 indicates mild to moderate, and 9–11 indicates severe 2). This scoring was validated in a 2017 validation 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 inflammation 6).
A prospective randomized comparative study showed that in patients who had decreased tear secretion and shortened tear film breakup time before transplantation, postoperative test values were better in the group that started cyclosporine eye drops 4 times a day 1 month before allogeneic hematopoietic stem cell transplantation and continued after transplantation than in the control group11). This was a small study completed by 58 patients, and the results do not establish uniform prophylactic administration for all patients.
If conservative treatment does not improve the condition, consider the following:
Mesenchymal stem cells (MSCs) have immunosuppressive effects and tissue regenerative capacity, and are being researched 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 being studied for application as cell-free 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 fibrotic reactions1)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 of attack1).
Destruction of the duct-acinar secretory unit: Fibrosis progresses and tear secretion capacity is lost.
Meibomian gland obstruction: T-cell-mediated MG epithelial cell damage and ductal epithelial hyperkeratosis are the main causes of obstructive MGD6).
Oxidative stress: Accumulation of lipofuscin-like inclusions causes oxidative damage to lacrimal gland acinar cells, reducing tear production6).
Corneal and conjunctival damage
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 in healthy individuals before HSCT, and further decreases with the onset of oGVHD. Increased NK1R expression is involved6).
Corneal nerve damage: Abnormal activation of the 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 or 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 used1).
MSCs produce the following immunomodulatory factors and suppress various immune cells involved in the pathogenesis of oGVHD3).
MSCs express apoptosis-inducing molecules such as PDL-1, PDL-2, and FasL, inducing caspase-3-dependent apoptosis of activated T cells and NK cells3).
Ye et al. reviewed the therapeutic effects of MSCs and MSC-derived exosomes (MSC-Exo) on oGVHD1). MSCs have the ability to differentiate into corneal epithelial cells and improve corneal damage through secretion of anti-inflammatory proteins such as TSG-61). Subconjunctivally injected human MSCs protect the cornea from T-cell invasion in oGVHD and also show effects in the contralateral eye1). MSC injection improved Schirmer values in 54.55% of cases6).
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 oGVHD3).
MSC-Exos, due to their lipid membrane and nanosize, can penetrate biological barriers in the eye and directly deliver cargo to damaged corneal epithelial cells and infiltrating leukocytes3). In a prospective clinical trial, MSC-Exos were administered to 28 eyes with refractory oGVHD-related dry eye, resulting in decreased fluorescein scores, prolonged TBUT, increased tear secretion, and reduced OSDI scores6). Amniotic fluid-derived MSC-Exos (AF-MSC-Exos) are rich in NGF and BDNF, which may contribute to retinal regeneration via neurotrophic factors3). While they may avoid unwanted differentiation associated with MSC transplantation, long-term safety has not been established in comparative clinical trials3).
In preclinical allogeneic hematopoietic stem cell transplantation models, the combination of regulatory T cells (Tregs) and BET inhibitors has been reported to increase Treg numbers and improve systemic GVHD scores6). Therapeutic efficacy for ocular GVHD has not been established.
However, further large-scale clinical trials are needed for the clinical application of MSC-Exos, and establishing the optimal dose, administration frequency, and long-term safety remain challenges1).
Bohlen et al. systematically reviewed 19 studies published between 2018 and 2023, comprehensively evaluating molecular biomarkers for oGVHD2). Cytokines, proteome, lipid profiles, leukocytes, and microbiota in tears were examined, with cytokine profiling being the most studied biomarker2).
Elevated ICAM-1, IL-6, and IL-8 may reflect disease severity, while decreased EGF and IL-7 may serve as useful biomarkers for differentiating oGVHD from dry eye2).
Tear lipid profiles (phosphatidylcholine, sphingomyelin, lactosylceramide) also show strong correlations with clinical parameters and are promising biomarker candidates2). Reduced diversity of the ocular surface microbiota has also been observed after HSCT, suggesting an association with the development of oGVHD2).
