Chronic Ocular Graft-versus-host Disease Research Articles

Ocular surface expression of inflammatory cytokines in GvHD and their association with disease development and clinical manifestations

The aim of this study was to investigate the tear cytokine profiles of patients with chronic ocular graft versus host disease (GvHD) and evaluate their association with clinical disease severity. Consecutive patients attending the Haematology clinic with a known or suspected diagnosis of chronic ocular GvHD were invited to participate. To be included, patients had to fulfil either or both of the National Institute of Health (NIH) or the International Chronic Ocular Graft‐vs‐Host‐Disease Consensus Group (ICCGvHD) diagnostic criteria.Clinical parameters recorded included best correct visual acuity (BCVA), Schirmers I test, tear break up time (TBUT), and Oxford surface staining (OSS) along with the overall grading of ocular GvHD severity as defined by the ICCGvHD. Ocular tear samples were collected and levels of cytokine production (IFN‐γ, IL‐1β, IL‐2, Il‐4, IL‐6, IL‐8, IL‐10, IL‐12p70, IL‐13, and TNF‐ α) were assayed using Meso Scale Discovery (MSD) multi‐array technology. The results were compared to those of healthy matched controls using unpaired t test. Results were correlated with clinical parameters using Pearson r correlation.Thirteen patients took part in the study (8 male, 61.5%; 5 female, 38.5%) with an average age of 43.9 years (±13.4). With regards to ocular examinations, patients were found to be heavily dependent on lubricant eye drops (average 8.5 times/day). Patients suffered from both aqueous deficient and evaporative DED with an average Schirmer's measurement of 4.2 mm (±5.7, range of 0–21) and average TBUT of 3.8 s (±1.3, range 1–6). The average Oxford surface staining score was 7.9 (±4.2, range of 0–15). According to the ICCGvHD grading system, and using the average data across both eyes, seven of the patients had ‘Mild/Moderate’ disease (53.8%) and the remainder had ‘Severe’ disease (n = 5, 38.5%).The levels of IFN‐γ, IL‐1β, IL‐2, IL‐6, IL‐8, IL‐10, IL‐12p70, IL‐13, and TNF‐ α were found to be statistically elevated when compared to healthy age and gender matched controls (FDR p value<0.05). In those with early‐stage disease (n = 5), IFN‐γ was found to strongly correlate with lubricant usage (0.98, p = 0.03), and IL‐2 with the severity of ocular surface staining grade (1.00, p = 0.03), implying that these cytokines in particular may play a role in the development of chronic ocular GvHD and represent promising treatment targets for patients in the initial stages of disease.This study demonstrates that ocular tear cytokines are elevated in patients with chronic ocular GvHD, reiterating the role of inflammation in the pathogenesis of disease. Furthermore, the correlation of IFN‐γ and IL‐2 with clinical parameters of disease severity suggest that these cytokines play a role in early disease development. These findings support the implementation of anti‐inflammatory treatment such as topical calcineurin inhibitors, in conjunction with tear replacement and preservation to avoid irreparable damage to the ocular surface, and this may be best utilized in the initial stages of the disease development.

Corneal complications of ocular GvHD

Corneal fluorescein staining is one of the tests recommended to diagnose and grade ocular graft versus host disease (GvHD) according to the International Chronic Ocular GvHD Consensus Group. Despite superficial punctate keratopathy is the most common corneal manifestation, patients with more severe stages may develop corneal neovascularization, sterile corneal ulceration and even perforation. Previous in vivo confocal microscopy (IVCM) studies reported significant microstructural changes in the cornea of patients with ocular GvHD, including a higher density of dendritic cells and globular immune cells, a network of hyper‐reflective activated keratocytes, and a lower density and higher tortuosity of sub‐basal corneal nerves. Dendritic cells act as antigen‐presenting cells, and play a key role in ocular surface immune homeostasis. Thus, their increased density may be indicative of immune activation and inflammation of the ocular surface in patients with ocular GvHD. Interestingly, Kheirkhah et al. reported higher dendritic cell density in patients with DED owing to systemic immune disease (i.e., Sjögren syndrome and ocular GvHD) compared to patients with DED of other origins. Recently, our group employed a fully automated IVCM analysis system to compare corneal sub‐basal nerve plexus in patients with DED owing to both ocular GvHD and Sjögren syndrome and in healthy control subjects. Although overall patients with DED showed lower density of nerve fibres and branches, shorter nerve fibres and higher fibre width compared to healthy controls, no significant difference was observed between patients with ocular GvHD and Sjögren syndrome for all IVCM metrics. In agreement with this observation, other studies reported no significant difference of IVCM parameters in DED patients with and without ocular GvHD after adjusting for clinical severity of dry eye. This suggests that the ocular surface changes observed by IVCM in ocular GvHD may be possibly reflective of the local disease severity rather than the underlying systemic process.

AAV-mediated expression of HLA-G for the prevention of experimental ocular graft vs. host disease

Ocular graft versus host disease (OGvHD) develops after allogeneic hematopoietic stem cell transplantation (HSCT) and manifests as ocular surface inflammatory disease. This study evaluated the efficacy of adeno-associated virus (AAV) gene therapy encoding human leukocyte antigen G (HLA-G) to inhibit OGvHD. A major histocompatibility mismatch chronic OGvHD murine model was evaluated. 7days after HSCT, mice were dosed subconjunctivally with scAAV8-HLA-G1/5 (1 x 109 vg/eye), topical cyclosporine (twice daily), or left untreated. Body weights and tear production (red thread test) were recorded, and eyelid, corneal opacity, and corneal fluorescein retention were scored through day 44 after HSCT. Tissues were collected for vector biodistribution, ocular histology, and immunofluorescence. Compared with untreated HSCT eyes, those dosed with scAAV8-HLA-G1/5 had significantly reduced clinical inflammatory signs of OGvHD. On histology, eyes that received scAAV8-HLA-G1/5 or cyclosporine had a significantly lower mean limbal mononuclear cell count when compared with non-treated HSCT eyes. HLA-G immunofluorescence was detected in the subconjunctiva and peripheral cornea in HSCT animals treated with scAAV8-HLA-G1/5. Vector genomes were detected in the lacrimal gland, but not in the other tested organs. These results provide evidence that subconjunctival AAV targets ocular surface and corneal disease and support that HLA-G-based gene therapy may be an effective treatment for OGvHD.

Multicenter prospective validation study for international chronic ocular graft-versus-host disease consensus diagnostic criteria

PurposeTo validate the international chronic ocular graft-versus-host disease (GVHD) diagnostic criteria (ICCGVHD) compared to the National Institute of Health diagnostic criteria 2014 (NIH2014) for chronic ocular GVHD. MethodsBetween 2013 and 2019, the study enrolled 233 patients with or without chronic ocular GVHD combined with the presence or absence of systemic chronic GVHD in an internationally prospective multicenter and observational cohort from 9 institutions. All patients were evaluated for four clinical parameters of ICCGVHD. ResultsThe relation between the ICCGVHD score (0-11) and NIH2014 eye score (0–4) was relatively high (r = 0.708, 95% CI: 0.637–0.767, p < 0.001). The sensitivity and specificity of ICCGVHD for NIH 2014 for 233 patients were 94.3% (95% CI: 89.6%–98.1%) and 71.7% (95% CI: 63.0–79.5%), respectively (cutoff value of the ICCGVHD score = 6). The positive predictive value was 77.1% (95% CI: 71.1%–82.1%), and the negative predictive value was 87.0% (95% CI:81.6–92.5%). For the patients with systemic GVHD (n = 171), the sensitivity and specificity were 94.2% and 67.2%, respectively (ICCGVHD-score cutoff value = 6). By receiver operating characteristic (ROC) curve analysis, the area under the curve (AUC) was 0.903 (95% CI: 0.859–0.948). For patients without systemic GVHD (n = 62), the sensitivity and specificity were 100% and 76.7%, respectively (ICCGVHD-score cutoff value = 6). The AUC was 0.891 (95% CI 0.673–1.000). ConclusionsGood sensitivity, specificity, predictive value and correlation were found between ICCGVHD and NIH2014. ICCGVHD scores ≥6 can be useful to diagnose ocular GVHD with or without systemic GVHD for clinical research.

Biomarkers in Ocular Graft-Versus-Host Disease: Implications for the Involvement of B Cells

Graft-versus-host disease (GVHD) is an immune-mediated inflammatory disease resulting from destruction of host tissue by donor immunoreactive cells and occurs in 30% to 70% of post-hematopoietic stem cell transplantation (HSCT) patients. Ocular involvement occurs in up to 60% to 90% of patients with chronic GVHD. T cells have long been recognized as a key driver of alloreactivity in chronic ocular GVHD (oGVHD). However, the role of B-cells has not been elucidated. To further explore the involvement of B-cells in the immune mechanism of chronic oGVHD and to uncover more sensitive biomarker indicators, we conducted this study on the tear cytokine analysis of chronic oGVHD. The study enrolled 18 patients (27 eyes) diagnosed with chronic oGVHD and 11 patients (22 eyes) diagnosed with dry eye disease (DED) as a control group. The microsphere-based immunoassay was used to determine 29 tear cytokines in both groups. Spearman's test was used to analyze the correlation between cytokine levels and different ophthalmic indexes (National Institutes of Health eye score, fluorescein tear film break-up time, corneal fluorescein staining, and Schirmer's test). Receiver operating characteristic curves were used to assess the predictive potential of the identified cytokines for chronic oGVHD. Twenty tear cytokine levels were elevated in patients with chronic oGVHD compared to those with DED (P < .05). Proliferation-inducing ligand (APRIL) and epidermal growth factor showed lower levels in patients with chronic oGVHD. Ultimately, IL-2, 6, and 8, ICAM-1 (CD54), E-selectin (CD62E), neuropilin-1, and B-cell activation factor (BAFF) levels had a strong correlation with ophthalmic indexes and an area under the curve (AUC) > 0.85. BAFF/APRIL exhibited superior diagnostic capabilities (AUC = 0.995; 95% confidence interval, 0.983-1.000). Our study identified IL-2, 6, 8, ICAM-1, CD62E, E-selectin, neuropilin-1, and BAFF as promising tear biomarkers that can indicate the severity of chronic oGVHD. Notably, APRIL/BAFF shows superior diagnostic capabilities, revealing that B cells may play an important role as immune substrates in chronic oGVHD. © 2023 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Ocular Findings of Pediatric Dry Eye Related to Graft-Versus-Host Disease

Objectives:To evaluate the frequency and findings of dry eye associated with ocular graft-versus-host disease (GVHD) in pediatric hematopoietic stem cell transplantation (HSCT) patients.Materials and Methods:Retrospectively the records of pediatric patients with ocular GVHD were evaluated and ophthalmologic examination findings as well as Schirmer test results, tear film break-up time, and corneal staining grades were recorded. In severe dry eye patients topical cyclosporine-A was prescribed and the results were evaluated.Results:GVHD was detected in 51 (23.4%) of 218 HSCT patients, 4 of whom died during follow-up. Thirty (63.8%) of the remaining 47 patients had chronic ocular GVHD and 4 patients with severe dry eye were treated with topical cyclosporine-A with a median follow-up of 12.1 months. Severe dry eye symptoms and findings significantly improved in 2 patients. However, 1 patient had to stop treatment due to side effects.Conclusion:In children, chronic ocular GVHD is a common finding of GVHD after HSCT. Therefore, these patients should be examined periodically for dry eye.

Long-term Outcomes of Cataract Surgery in Patients With Chronic Ocular Graft-Versus-Host Disease.

The aim of this study was to evaluate the outcomes of cataract surgery in patients with chronic ocular graft-versus-host disease (GVHD). A retrospective review was performed on 77 eyes of 42 patients with chronic ocular GVHD that underwent cataract surgery between January 2014 and February 2020 in a tertiary institution. Posterior subcapsular cataract was seen in 53 (68.8%) of 77 eyes, with a mean preoperative corrected distance visual acuity (CDVA) of 0.61 ± 0.49 logarithm of the minimum angle of resolution (logMAR). Postoperatively, with a mean follow-up of 21 months, CDVA improved to 0.17 ± 0.22 logMAR at the latest visit (P < 0.0001). With latest available refraction, 42 (57.5%) of 73 eyes were within 0.5 diopters of target refraction, and 59 eyes (80.8%) were within 1.0 diopter. Postoperative complications included superficial punctate keratopathy within 1 month postoperatively (19 eyes, 24.7%), posterior capsular opacification requiring yttrium-aluminum-garnet (YAG) laser capsulotomy (36 eyes, 46.8%), corneal epithelial defect (7 eyes, 9.1%), filamentary keratopathy (5 eyes, 6.5%), cystoid macular edema (3 eyes, 3.9%), and infectious crystalline keratopathy (1 eye, 1.3%). Lower preoperative National Institutes of Health ocular GVHD severity scores were associated with a better postoperative CDVA (grade 1, 0.13 ± 0.16 logMAR; grade 2, 0.16 ± 0.23 logMAR; and grade 3, 0.36 ± 0.21 logMAR; P = 0.004). Cataract surgery improves visual acuity long term in most patients with chronic ocular GVHD. Close postoperative monitoring is important to detect ocular surface inflammation secondary to chronic ocular GVHD, particularly in severe ocular GVHD.

Incidence, Risk Factors and Complications of Ocular Graft-Versus-Host Disease Following Hematopoietic Stem Cell Transplantation

The purpose of this research was to evaluate the incidence, risk factors, and complications of ocular graft-versus-host disease (GVHD) in a large single-center study. Retrospective observational case series. This study included 283 patients who underwent hematopoietic stem cell transplantation (HSCT) between 2005 and 2020. Ocular GVHD was diagnosed according to International Chronic Ocular GVHD Consensus Group criteria. Potential risk factors for ocular GVHD were evaluated using the Cox proportional hazards model. The cumulative incidence of ocular GVHD was 19.7% at 1 year, 29.3% at 2 years, 40.7% at 3 years, 47.2% at 4 years, and 49.7% at 5 years. Ocular GVHD was significantly associated with recipient age (hazard ratio [HR]: 1.228; 95% confidence interval [CI]: 1.033-1.459; P=.020); female sex (HR: 1.797; 95% CI: 1.195-2.703; P=.005); peripheral blood stem cell use (PBSC) (HR: 2.079; 95% CI: 1.268-3.411; P=.004); and previous acute GVHD (HR: 1.276; 95% CI: 1.073-1.518; P=.006). Ocular complications after HSCT included cataract, corneal ulcer, corneal perforation, lacrimal obstruction, herpetic keratitis, and cytomegalovirus retinitis. Half of patients developed ocular GVHD in the 5 years following HSCT. Older age, female sex, use of PBSC, and acute GVHD disease were significant predictors of ocular GVHD. Hematologists and ophthalmologists should be aware of its vision threating complications.

Tear cytokine levels in the diagnosis and severity assessment of ocular chronic graft-versus-host disease(GVHD)

PurposeTo analyse the tear cytokine levels of patients diagnosed with ocular chronic graft-versus-host disease(GVHD)and examine the consistency of these levels with different ocular surface parameters. Methods23 ocular chronic GVHD patients were selected for the assessment of tear cytokine levels and ocular surface parameters (TBUT, CFS, OSDI, and Schirmer's test), and 16 dry eye disease(DED)patients without systemic immune disease were selected as the control group. The 23 cytokines were measured using microsphere-based immunoassay analysis and their consistency with different ocular surface parameters was studied. ResultsICAM-1, IL-1β, IL-6, and IL-8 showed elevated levels in the eyes of oGVHD patients compared to DED [P < 0.001]. IL-7 and EGF showed lower levels in the eyes of patients with oGVHD than in those of patients with DED [P < 0.0001]. Furthermore, the levels of IL-6 and IL-8 showed a stronger correlation with corneal fluorescein staining (CFS) (P < 0.05), and the levels of IL-6 and ICAM-1 were most consistent with fluorescein tear film break-up time (TBUT) (P < 0.05). ConclusionsOur study demonstrated certain tear cytokines, including ICAM-1, IL-1β, IL-6, IL-8 IL-7 and EGF, as promising new possible diagnostic markers of chronic oGVHD and criteria for chronic ocular GVHD severity. Because tear sampling is noninvasive and simple, this method is expected to be an overwhelming applicable for the screening and diagnosis of chronic GVHD.

Corneal higher-order aberrations in eyes with chronic ocular graft-versus-host disease

PurposeChronic ocular graft-versus-host disease (GVHD) is a long-term complication after hematopoietic stem cell transplantation (HSCT) and leads to irreversible visual morbidity due to severe ocular surface impairments including visual disfunction. However, knowledge about the optical function in chronic ocular GVHD is limited because it is difficult to assess quantitative optical function objectively. The development of anterior segment optical coherence tomography has allowed objective quantification of optical function by evaluating corneal higher-order aberrations (HOAs). Therefore, we applied this quantification in chronic ocular GVHD patients and verified the correlation between corneal HOAs and visual acuity. MethodsWe retrospectively reviewed chronic ocular GVHD patients and the recipients after HSCT. Then, analyzed the relationship between visual function and the severity of chronic ocular GVHD. ResultsThe eyes of patients with chronic ocular GVHD had higher corneal HOAs than those of non-GVHD patients (HOAs; 0.481 ± 0.306 vs 0.254 ± 0.084, and 0.917 ± 0.609 vs 0.529 ± 0.130. P < 0.001, and 0.002. 4-mm and 6-mm diameters respectively. Corneal HOAs were correlated with the severity of chronic ocular GVHD (r = 0.436. P < 0.001). Moreover, corneal HOAs were correlated with visual acuity, especially in eyes with severe chronic ocular GVHD cases (HOAs; 4-mm r = 0.636. P = 0.036. Total 6-mm r = 0.871. P =<0.001). ConclusionsWe succeed to assess the objective value in the optical function of the chronic ocular GVHD. Quantification of corneal HOAs could be an objective evaluation to assess optical function in eyes with chronic ocular GVHD.

Ocular instillation of vitamin A–coupled liposomes containing HSP47 siRNA ameliorates dry eye syndrome in chronic GVHD

AbstractChronic graft-versus-host disease (GVHD) profoundly affects the quality of life of long-term survivors of allogeneic hematopoietic stem cell transplantation (SCT). The eyes are frequently involved, and dry eye syndrome is the most common manifestation of ocular chronic GVHD. We explored the role of heat shock protein 47 (HSP47) in ocular GVHD and developed a novel antifibrotic topical therapy using vitamin A–coupled liposomes containing HSP47 small interfering RNA (siRNA) against HSP47 (VA-lip HSP47). In a mouse model of chronic GVHD, infiltration of HSP47+ fibroblasts and massive fibrosis surrounding the lacrimal ducts were observed after allogeneic SCT, leading to impaired tear secretion. After ocular instillation, VA-lip HSP47 was distributed to the lacrimal glands, knocked down HSP47 expression in fibroblasts, reduced collagen deposition, and restored tear secretion after allogeneic SCT. Ocular instillation of VA-lip HSP47 also ameliorated established lacrimal gland fibrosis and dry eye syndrome. VA-lip HSP47 eye drops are a promising prophylactic and therapeutic option against dry eye syndrome in chronic GVHD.

Commensal microflora in human conjunctiva; characteristics of microflora in the patients with chronic ocular graft-versus-host disease

PurposeTo investigate the transformation in the composition of ocular surface microflora. Evidence shows that microbial diversity correlates with autoimmune disorders. Chronic ocular graft-versus-host disease (GVHD) is the lethal complication after hematopoietic stem cell transplantation (HSCT) which influences patients’ quality of life. It has a similar pathophysiology to autoimmune disorders but the relation of the microbial status especially in the ocular surface and chronic ocular GVHD is still unknown. MethodsWe prospectively harvested conjunctival microorganism with a cotton swab from following 3 groups, 32 eyes/20 ocular GVHD patients (9 males, 11 females), 28 eyes/20 nonGVHD cases (10 males, 10 females) which defined as post hematopoietic stem cell transplantation and without ocular GVHD, and 20 eyes/11 controls (7 males, 4 females). Conventional culture-based methods were performed to examine the microbial community. ResultsOcular surface microbes in the GVHD patients was more complex in diversity compared with in the nonGVHD patients and the control. Staphylococcus species, Alpha-haemo Streptococcus, Corynebacterium species, Propionibacterium Acnes, Aerobic gram-positive cocci, Haemophilus Influenzae, and Aerobic gram-positive rod were observed in the GVHD patients, whereas only a few species detected in the other groups. ConclusionsWe found that ocular surface microbes in the GVHD patients is more diverse than that in the nonGVHD patients and the controls. These results suggest the alternation of microbes are involved in the pathogenic process of the chronic ocular GVHD. Further examination using state-of-the-art methods will be needed to gain greater insights into the diversity of microflora on the chronic GVHD-affected ocular surface.

Clinical Manifestations and Prognostic Factors of Chronic Ocular Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

Introduction:Ocular graft-versus-host disease (GvHD) is a common complication of allogeneic hematopoietic stem cell transplantation (alloHSCT), typically affecting 40-60% of patients within 3 years after alloHSCT. The most common clinical manifestation is dry eye disease (DED), which may lead to secondary epithelial changes in the cornea such as filamentary keratitis, and contribute to ocular discomfort and further complications. Patients with DED typically require a complete ophthalmologic examination, including a slit lamp exam to look at punctate epithelial erosions (PEEs) and other ocular surface findings. Treatment for chronic ocular GvHD typically ranges from artificial tears and lid hygiene, to anti-inflammatory agents such as corticosteroids or cyclosporine A, and BostonSight Prosthetic Replacement of the Ocular Surface Ecosystem (PROSE) or other scleral lens therapy. Here, we retrospectively describe the clinical manifestations and look at potential prognostic factors of ocular GvHD at our institution.Methods:We identified 113 patients who had undergone alloHSCT by a single hematologist at the Norris Comprehensive Cancer Center from 1/14/2014 to 12/26/2017. Patients were excluded if they had no documented ocular symptoms or no eye exam performed. We created a final cohort of 26 patients whose demographics, transplant-related factors, clinical manifestations, and treatment outcomes were collected. PEE, from the optometrist's perspective, was graded from 0 - 4 with 4 being the most severe, and ocular surface disease index (OSDI), from the patient's perspective, was graded from 0 to 100 with 100 being the most severe. Descriptive statistics were used to characterize the cohort. The T-test was used to describe groups with continuous outcomes and the Fisher's exact test was used to describe groups with categorical outcomes. A p-value of < 0.05 was considered statistically significant.Results:The incidence of ocular symptoms in our study was 30.1%. A total of 26 patients (mean age 43 years old) with 84.6% Hispanic, 11.5% non-Hispanic Whites (NHWs), and 3.8% African American, were included in statistical analysis. The primary disease included 50% acute myeloid leukemia (AML), 30.7% acute lymphoid leukemia (ALL), 7.7% severe aplastic anemia (sAA), chronic myelomonocytic leukemia (CMML), myelofibrosis, and hemophagocytic lymphohistiocytosis (HLH). 50% of the patients underwent alloHSCT with a match related donor (MRD), 34.6% with a match unrelated donor (MUD), and 15.4% of patients with a haploidentical donor (HAPLO). 65.4% of patients had evidence of acute GvHD and 100% of patients had evidence of chronic GvHD in other organs.The most common symptom was DED (73%), followed by light sensitivity (34.6%), gritty sensation (30.8%), eye pain (30.8%), itchy eyes, mucus discharge, foreign body sensation, and tearing. There was a significantly higher PEE score for patients with the A blood type compared to the other blood types (2.0 vs. 0.98; p < 0.0046) and a not statistically significant trend towards higher OSDI scores as well (50.1 vs. 27.3; p = 0.071). There also was a significantly higher OSDI score in patients with donors > 50 years old (65.0 vs. 32.2; p = 0.045) and a significantly higher proportion of filamentary keratitis (66.6% vs. 5%; p = 0.0047), with a statistically insignificant trend towards higher PEE scores (1.92 vs. 1.36; p = 0.2). No prognostic impact was seen with primary disease type, race, age of recipient at transplant, gender of donor or recipient, recipient blood type, type of transplant, CMV status of donor or recipient, recipient CMV reactivation post-transplant, prior acute GvHD or concurrent systemic chronic GvHD.Artificial tears/conservative therapy was recommended in 15.4% of patients, anti-inflammatory eye drops in 42.3% and scleral lens/PROSE therapy in 42.3% of patients. Compliance was poor and only 14 patients had visual acuity data with treatment. There was an improvement in LogMar score of average 0.14 in both eyes (0.08 in right eye and 0.19 in left eye).Conclusions:Ocular GvHD is an important complication in patients undergoing alloHSCT. Patients who had type A blood type had a significantly higher PEE score than those with other blood types. There was also a significantly higher OSDI score in patients who had donors > 50 years of age, as well as a significantly higher proportion of filamentary keratitis, which can lead to severe corneal complications. DisclosuresNo relevant conflicts of interest to declare.

Sjögren's Syndrome, Non-Sjögren's Syndrome, and Graft-Versus-Host Disease Related Dry Eye.

I have reviewed available literature on dry eye related to Sjögren's syndrome (SS), non-Sjögren's syndrome (non-SS), and graft-versus-host disease (GVHD) to examine aqueous tear deficient dry eye as a subtype of dry eye. This section will focus on clinical studies regarding those subtypes of dry eye. I searched the PubMed database from 1990-2017 for discussion of clinical features, diagnostic criteria, and risk factors of SS, non-SS, and GVHD-related dry eye. In addition, therapeutic options for each subtype of dry eye are described. Although the clinical presentations of SS and chronic graft-versus-host disease (cGVHD) are similar, ocular surface fibrotic changes are characteristic of ocular GVHD but not SS- or non-SS-related dry eye. Recently, diagnostic criteria for each disease have been proposed and include the American College of Rheumatology/European League Against Rheumatism (ACR-EULAR) for SS and the International Chronic Ocular GVHD consensus criteria. Although there has been gradual progress, there are currently no specific therapies and few approved treatment options for these intractable diseases, including SS and GVHD. As judged by the findings, these subtypes of dry eye are different clinical entities from simple dry eye. Therefore, novel therapies, specific to these subtypes of dry eye, may be required in the future.

Single-Center Retrospective Study on Meibomian Gland Loss in Patients With Ocular Chronic Graft-Versus-Host Disease.

This study aimed to analyze the influencing factors of meibomian gland loss in patients with ocular chronic graft-versus-host disease (GVHD) and its correlation with other clinical ocular surface assessment indexes. The clinical data of patients with ocular chronic GVHD from the ocular surface and corneal outpatient clinic of the First Affiliated Hospital of Soochow University were reviewed from June 2012 to June 2016. The relationship between the percentage of meibomian gland acinar area and the influencing factors, such as patient's sex, age, transplantation method, human leukocyte antigen (HLA) matching, the time when eye discomfort appeared after transplantation (month), and the severity of ocular chronic GVHD, was investigated. Moreover, the correlation between the percentage of meibomian gland acinar area and other ocular surface assessment indexes, such as subjective ocular symptom score, eyelid margin score, tear film break-up time, corneal and conjunctival staining score, and the Schirmer test, was analyzed. A linear relationship was found between the percentage of meibomian gland acinar area and the severity of ocular chronic GVHD, but no linear relationship existed between the percentage of meibomian gland acinar area and the factors such as sex, age, transplantation method, HLA matching, and the time when eye discomfort appeared after transplantation. A negative correlation was observed between the percentage of meibomian gland acinar area and eyelid margin score. The percentage of meibomian gland acinar area can reflect the severity of ocular chronic GVHD. The clinical significance of the percentage of meibomian gland acinar area needs further investigation.

Eyelid metrics assessment in patients with chronic ocular graft versus-host disease

PurposeTo assess eyelid metrics in the setting of chronic ocular graft versus-host disease (oGVHD), and to further correlate them with hematological and ocular characteristics. MethodsProspective case-control study conducted at a single tertiary-referred Center. The following eyelid tests were performed in oGVHD patients and control subjects: vertical lid pull; anterior/lower distraction; lateral/medial distraction; distance between lateral canthal angle and orbital rim; margin reflex distances (MRD) 1 and 2; duration of tarsus exposure; snap back. Correlations of eyelid metrics with hematological and ocular parameters in the oGVHD group were performed. ResultsTwenty-seven patients with oGVHD and 27 healthy matched subjects were finally included. Significantly higher values of vertical lid pull, anterior/lower distraction, lateral/medial distraction, and distance between lateral canthal angle and orbital rim were found in the oGVHD group compared to controls (always p < 0.02). Conversely, MRD1 was lower in oGVHD patients compared to controls (p < 0.001). Duration of tarsus exposure and snap back test were pathological in a higher percentage in oGVHD group compared to controls (respectively 66.7 and 59.3% vs 33.3 and 25.9%; p < 0.005). Vertical lid pull test was significantly higher in oGVHD patients with superior limbic keratoconjunctivitis (13.8 ± 2.4 vs 10.9 ± 2.4, p = 0.010). Ocular GVHD patients with subtarsal fibrosis had a higher percentage of pathological values for duration of tarsus exposure test (77.3 vs 20.0%; p = 0.014). ConclusionsThe present study highlighted for the first time higher eyelid laxity in oGVHD patients. This intriguing association may add a further piece to the puzzle of clinical features occurring in the setting of oGVHD.

Ocular chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation in an Italian referral center

PurposeThis study aimed to assess the prevalence and clinical manifestations of ocular graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods269 patients who received allo-HSCT for hematologic malignancies were evaluated between December 2013 and April 2017 in this prospective observational study. Subjects underwent ophthalmologic examination at 6, 12 and 24 months after allo-HSCT. We evaluated the ophthalmologic and hematological data using the NIH consensus criteria definition and the International Chronic Ocular GVHD Consensus Group scoring systems. ResultsAccording to NIH consensus criteria definition, ocular GVHD developed in 46.1%, 51.9% and 54.7% of patients at the follow-up visits. According to the International Chronic Ocular GVHD Consensus Group, ocular GVHD developed in 41.3%, 47.7% and 51.9% of patients at the follow-up visits. We found a strong association between the presence of systemic GVHD and the development of chronic ocular GVHD throughout the entire follow-up period. Weaker associations were found between the presence of a female donor, matched related donor, conjunctival hyperemia and conjunctival fibrosis. ConclusionsMore than 50% of subjects develop chronic ocular GVHD after allo-HSCT. The presence of active systemic GVHD, female donor and matched related donor are associated with ocular GVHD development.

A Review of Ocular Graft-Versus-Host Disease.

: Graft-versus-host disease (GVHD) is a major complication that occurs following allogeneic hematopoietic stem cell transplantation, which is a potential curative therapy used in a variety of malignant or benign hematological diseases. Graft-versus-host disease primarily occurs in many organs, but most notably in the skin, lungs, gastrointestinal tract, liver, eyes, mucosa, and musculoskeletal system. Ocular manifestations of GVHD may precede other systemic GVHD findings, and it may be a poor prognosis for mortality. While all parts of the eye may be affected, ocular GVHD occurs primarily in the ocular surface. Dry eye disease or keratoconjunctivitis sicca is the most common presenting manifestation of chronic ocular GVHD. Dry eye disease in ocular GVHD is a multifactorial process, which involves destruction and fibrosis of lacrimal glands and conjunctiva, leading to tear film deficiency and instability. Depending on the severity of ocular involvement and response to treatment, ocular GVHD may cause decreased quality of life. Management of GVHD begins with prevention by understanding risk factors and by implementing prophylactic treatment after allogeneic hematopoietic stem cell transplantation. A multidisciplinary approach to the prevention and treatment of GVHD is important, and there are currently no preventive therapies available for ocular GVHD. Once diagnosed, ocular GVHD treatment strategies target ocular surface lubrication and support, tear film stabilization, inflammation reduction, and surgical intervention. The goal of this review is to define ocular GVHD and its categorical manifestations, as well as to describe the importance of comprehensive assessment, diagnosis, and ophthalmologic treatment and management of ocular GVHD with a multidisciplinary approach.

Treatment of severe chronic ocular graft-versus-host disease using 100% autologous serum eye drops from a sealed manufacturing system: a retrospective cohort study.

To analyse patients with chronic ocular graft-versus-host disease (GvHD) under treatment with 100% autologous serum eye drops from a sealed manufacturing system. 17 patients with chronic ocular GvHD received 100% autologous serum eye drops from single use vials manufactured in a sealed system. Retrospective analysis included visual acuity, corneal staining, frequency of artificial tears, ocular symptoms by means of a questionnaire and information on subjective side effects and cost compensation. Data of prior to autologous serum eye drops therapy and at a 6-month follow-up were obtained. They demonstrated a significant increase in visual acuity (logMAR oculus dexter/right eye (OD) 0.5±0.32 to 0.4±0.3; oculus sinister/left eye (OS) 0.6±0.35 to 0.3±0.35; p=0.177/0.003) and significant improvement in corneal staining (Oxford grading scheme: OD from 3±1.03 to 2±1.43, OS from 4±1.0 to 2±1.09, p=0.004/0.001) and ocular symptoms (ocular surface disease index: 88±20.59 to 63±22.77; p=0.02). Frequency of artificial tears was reduced and no side effects were reported. Patient satisfaction was 100%, and cost compensation by health insurance reached 80%. 100% autologous serum eye drops using a sealed manufacturing system were efficient in improving the ocular surface, patient symptoms and visual acuity without side effects. It seems to be safe to use 100% autologous serum despite earlier suspicions regarding immune complex accumulations and exacerbation of ocular surface inflammation. The potential effects of serum levels of systemic immunosuppressives through readministration onto the ocular surface need to be elucidated.

Cataract surgery in patients with chronic severe graft-versus-host disease

To evaluate the surgical outcomes of cataract extraction with phacoemulsification and intraocular lens implantation in patients with severe chronic ocular graft-versus-host disease (GVHD). University of South Florida Eye Institute, Tampa, Florida, USA. Retrospective case study. A chart review was performed to identify patients with clinically severe, biopsy-proven chronic ocular GVHD who had cataract extraction. Outcome parameters included preoperative andpostoperative corrected distance visual acuity (CDVA), type of cataract, postoperative complications, type of underlying malignancy, and time from bone marrow transplant to cataract extraction. This study comprised 10 eyes of 6 patients with severe GVHD. Posterior subcapsular cataract accounted for all cataracts that were surgically removed in this patient cohort. The mean preoperative CDVA was 20/84, which improved to 20/30 at the 1-month postoperative visit and remained stable at 20/28 at the final visit noted in the charts (both P<.05). Two patients developed postoperative corneal melting. All but 1 patient had improved visual acuity after surgery. With meticulous preoperative biometric measurements and calculations and aggressive assessment and treatment of dry-eye syndrome, patients with severe ocular GVHD who had cataract extraction had excellent postsurgical refractive outcomes. Postoperative corneal melting was a complication seen with greater frequency than anticipated in this patient cohort. None of the authors has a financial or proprietary interest in any material or method mentioned.