Ocular Graft-versus-Host Disease after Hematopoietic Cell Transplantation: Expert Review from the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation.

Ocular graft-versus-host disease (GVHD) occurs in more than one-half of patients who develop chronic GVHD after allogeneic hematopoietic cell transplantation (HCT), causing prolonged morbidity that affects activities of daily living and quality of life. Here we provide an expert review of ocular GVHD in a collaboration between transplantation physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Recent updates in ocular GVHD regarding pathophysiology, preclinical models, risk factors, prevention, screening, diagnosis, response criteria, evaluation measures, and treatment are discussed. Ocular GVHD involves at least 3 biological processes: lacrimal gland dysfunction, meibomian gland dysfunction, and corneoconjunctival inflammation. Preclinical models have identified several novel pathogenic mechanisms, including the renin angiotensin system and endoplasmic reticulum stress signaling, which can be targeted by therapeutic agents. Numerous studies have identified reliable tests for establishing diagnosis and response assessment of ocular GVHD. The efficacy of systemic and topical treatment for ocular GVHD is summarized. It is important that all health professionals caring for HCT recipients have adequate knowledge of ocular GVHD to provide optimal care.

Spectral-domain optical coherence tomography evaluation of vitreoretinal adhesions in idiopathic epiretinal membranes.

BACKGROUND: Vitreoretinal adhesions play a key role in the vector forces exerted on the vitreoretinal interface, leading to tractional retina deformation and macular hole formation. The aim of this study was to identify the presence of vitreopapillary and vitreofoveal adhesions in idiopathic epiretinal membranes (ERMs) with spectral-domain optical coherence tomography (SD-OCT) and to evaluate their influence on the vitreoretinal interface. METHODS: Sixty-five eyes (65 patients) with idiopathic ERM and 64 healthy eyes (64 patients) underwent SD-OCT analysis. We studied vitreopapillary and vitreofoveal adhesion prevalence in eyes with idiopathic ERM using different SD-OCT patterns ("adherent" or "tractional"). We analyzed their influence on central foveal thickness (CFT), on retinal nerve fiber layer (RNFL) thickness, and on morphological modifications (foveal depression profile and inner/outer photoreceptor junction). RESULTS: Vitreopapillary adhesion was present in 51.6 % of normal eyes and in 24.6 % of eyes with idiopathic ERM, while vitreofoveal adhesion was found in 14.1 % of normal eyes and in 15.4 % of eyes with ERM. Vitreopapillary adhesion prevalence was significantly higher in the tractional ERM subgroup (p = 0.01), than in the adherent ERM subgroup. Both adhesions had no influence on CFT, RNFL thickness, or inner segment/outer segment junction status. CONCLUSIONS: Our study suggests that vitreoretinal adhesions may influence the pathogenesis and course of idiopathic ERM. The absence of vitreopapillary adhesion in the adherent type, and its presence in the tractional type, seems to play a key role in ERM characterization.

Conjunctival Matrix Metalloproteinase-9 Clinical Assessment in Early Ocular Graft versus Host Disease.

PURPOSE: Graft versus Host Disease (GVHD) typically affects the ocular surface, with a presentation resembling Dry Eye Disease (DED). Although the etiopathology is not completely known, the conjunctiva might be a key site of T-cell activation. The differential diagnosis might be tricky at early stages, because of the lack of dedicated clinical and laboratory tests. To meet these needs, we evaluated the suitability of ocular surface matrix metalloproteinase-9 (MMP-9) clinical test. METHODS: Consecutive GVHD patients, referred to IRCCS San Raffaele Scientific Institute, were recruited. DED patients served as controls. MMP-9 was tested through InflammaDry immunoassay kit in both groups; Ocular Surface Disease Index (OSDI) questionnaire, tear osmolarity, fluorescein Tear Break-up Time (TBUT), corneal and conjunctival staining, and Schirmer test I were also collected. Parametric and nonparametric statistical tests were used to analyze the intergroup differences; Receiver Operating Characteristics (ROC) curve analysis was carried out to perform sensitivity and specificity evaluations. RESULTS: Forty-five GVHD and 40 DED patients were included. MMP-9 expression was significantly higher in GVHD group than in DED (84.4% vs 33%, p ≤ 0.001). Corneal and conjunctival staining scores resulted worse in GVHD than in DED (0.95 ± 1.16 vs 0.40 ± 0.63, p=0.02; 0.77 ± 0.42 vs 0.40 ± 0.49, p=0.0005, respectively). No significant differences regarded the other collected parameters. GVHD group was characterized by positive correlations between MMP-9 and conjunctival staining (rho = 0.55, p=0.0002) and between MMP-9 and OSDI (rho = 0.3, p=0.01); a faint inverse correlation was found between MMP-9 and Schirmer test (rho = -0.25, p=0.04). CONCLUSION: MMP-9 has a role in physiologic cellular remodeling; when a proinflammatory stimulus occurs, MMP-9 molecules are overreleased in the extracellular matrix. The positive expression of MMP-9 in GVHD may be interpreted as the consequence of a T-cell aggression against self-antigens and may be considered a reliable biomarker to detect ocular surface inflammation in GVHD, even in early stages of the disease.

Retinal and Choroidal Changes of Vitreoretinal Lymphoma from Active to Remission Phase after Intravitreal Rituximab.

To identify main qualitative and quantitative changes by spectral-domain optical coherence tomography (SD-OCT) in eyes with vitreoretinal lymphoma (VRL) shifting form active to remission phase, after intravitreal rituximab (IVR).SD-OCT scans retrospectively assessed for: hyperreflective retinal dots (HRD), intraretinal infiltration, subretinal infiltration, outer retina (OR) fuzzy borders, and pigment epithelium detachments (PED).Central macular thickness (CMT) and choroidal thickness (CT) were measured. These features were examined in active and in remission phase.Eighteen eyes of nine patients enrolled. Patients received 5.3 ± 2.1 IVR according to a 2-weekly or monthly schedule. In remission phase, presence of HRD (p = 0.02), intraretinal infiltration (p = 0.02), OR fuzzy borders (p = 0.01) significantly reduced. Treatment frequency did not influence rate of disappearance of these features. CMT (p = 0.04) and CT (P = 0.004) became thinner.Signs referable to lymphoma-induced inflammation (CMT, CT, HRD) and infiltration (intraretinal infiltrates, OR fuzzy borders) decreased in remission phase. Further comparative studies needed to identify the specific role of IVR in inducing these changes.

Ocular Toxicity of Mirvetuximab.

PURPOSE: To report the clinical features and outcomes of corneal toxicity following mirvetuximab soravtansine therapy. METHODS: Five patients who were treated with mirvetuximab soravtansine were evaluated in our hospital for ocular symptoms during a period of 5 months between December 2017 and April 2018. A complete ophthalmologic examination, including anterior segment infrared reflectance (AS-IR) and anterior segment optical coherence tomography (AS-OCT), was performed. RESULTS: All 5 patients were female (average age, 62.4 ± 5.5 years) and being treated for advanced epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. Both eyes were involved in each case. Patients complained of blurred vision (n = 5), ocular pain (n = 2), tearing (n = 5), foreign-body sensation (n = 4), and photophobia (n = 4). Slit-lamp examination demonstrated fine corneal subepithelial opacities, mainly involving the corneal periphery migrating toward the center. AS-IR revealed the presence of hyporeflective dots on the cornea, suggesting that they were cystic. AS-OCT confirmed the subepithelial location of lesions. In all patients, the cornea cleared, and visual acuity recovered fully with a short course of topical steroids and lubricants. CONCLUSIONS: Mirvetuximab soravtansine therapy can cause transient corneal toxicity. A short course of topical steroids can reduce the patient symptoms.

Ocular disorders in multiple myeloma patients: cross-sectional study of prevalence and association with treatment.

Multiple myeloma (MM) therapy is evolving, and several new drugs are now available, extending patients' life and exposure to different compounds and toxicities. We conducted a cross-sectional observational study enrolling 93 consecutive patients on active treatment for MM, aiming to assess their ocular complications. All the patients underwent a comprehensive ophthalmic evaluation. In our cohort, prevalence of low visual acuity was in line with similar age healthy population reported in registry studies. Interestingly, we recorded a higher prevalence of lens opacities (46%) and dry eye syndrome (53%). Nevertheless, we did not find any significant association between ocular disorders and anti-myeloma treatments, even steroid therapy. This observation suggests that other factors besides treatments, such as M-protein deposition in eye structures, may have a role in developing ocular toxicities. Since MM patients are elderly patients at higher risk of age-related eye disorders, we recommend periodic ophthalmic assessment in daily practice.

Ocular graft-versus-host disease after hematopoietic cell transplantation: Expert review from the Late Effects and Quality of Life Working Committee of the CIBMTR and Transplant Complications Working Party of the EBMT.

Ocular graft-versus-host disease (GVHD) occurs in more than half of patients who develop chronic GVHD after allogeneic hematopoietic cell transplantation (HCT), causing prolonged morbidity, which affects activities of daily living and quality of life. Here we provide an expert review of ocular GVHD in a collaboration between transplant physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Recent updates in ocular GVHD, regarding pathophysiology, preclinical models, risk factors, prevention, screening, diagnosis, response criteria, evaluation measures, and treatment are discussed in this review. Ocular GVHD has at least three biological processes: lacrimal gland dysfunction, meibomian gland dysfunction, and corneoconjunctival inflammation. Preclinical models have found several novel pathogenic mechanisms, including renin angiotensin system and endoplasmic reticulum stress signaling that can be targeted by therapeutic agents. Many studies have identified reliable tests for establishing diagnosis and response assessment of ocular GVHD. Efficacy of systemic and topical treatment for ocular GVHD is summarized. It is important for all health professionals taking care of HCT recipients to have adequate knowledge of ocular GVHD for optimal care.

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

PURPOSE: This study aimed to assess the prevalence and clinical manifestations of ocular graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: 269 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. RESULTS: According 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. CONCLUSIONS: More 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.

Dexamethasone intravitreal implant in serpiginous choroiditis.

BACKGROUND/AIMS: To assess the efficacy and safety of dexamethasone (DEX) intravitreal implant in patients with active serpiginous choroiditis (SC) already receiving maximal tolerated systemic immunosuppressive therapy. METHODS: In this retrospective longitudinal study we evaluated patients receiving 0.7 mg DEX intravitreal implant for active SC despite maximal systemic immunosuppression. Medical history was reviewed over a period of 18 months for each patient. We diagnosed SC activity using direct fundus examination and blue-light fundus autofluorescence. Primary outcomes were the rate of disease control and functional changes at end of follow-up. Secondary outcomes were the incidence of injection-related adverse events and the success of immunosuppression tapering at the last examination. RESULTS: We examined eight eyes of seven patients. We controlled SC activity with one injection in five eyes, two injections in one eye, and three injections in two eyes (total of 13 implants). Best-corrected visual acuity at the end of the investigational period improved in two eyes (25%), remained stable in four eyes (50%) and decreased in two eyes (25%). Three eyes showed transient intraocular pressure increase and two eyes disclosed cataract progression. The average dosage of systemic prednisone at baseline and after DEX intravitreal implant decreased from 8.8 to 2.8 mg/day. CONCLUSIONS: Dexamethasone intravitreal implant may be an effective treatment option to control active serpiginous lesions in patients in whom increased systemic corticosteroid therapy is contraindicated.

Long-term treatment with rituximab in severe juvenile idiopathic arthritis-associated uveitis.

BACKGROUND/AIMS: To evaluate retrospectively the long-term efficacy of rituximab in patients with severe juvenile idiopathic arthritis (JIA)-associated uveitis. METHODS: Eight patients (15 eyes) with severe and longstanding JIA uveitis, who had an inadequate response in controlling uveitis to one or more biologic agents including tumour necrosis factor blockers and abatacept, received rituximab therapy. Rituximab was given at a dose of 1000 mg per infusion on days 1 and 15 and then every 6 months. Clinical responses to treatment, including decrease in uveitis activity, visual acuity changes, reduction of concomitant local and systemic corticosteroid and/or immunosuppressants, and occurrence of adverse events, were assessed. RESULTS: Eight patients with a mean±SD age of 22.8±5.5 years were treated. The mean ocular disease duration was 17.7 years; the mean±SD follow-up time on rituximab was 44.75±4.9 months; and the mean number of rituximab infusions received was 8.75 (range 6-12). All patients achieved complete control of uveitis, but in two patients rituximab was discontinued due to inefficacy in treating arthritis. The decrease in uveitis activity was evident 4-5 months after the first infusion. Systemic corticosteroids and immunosuppressants used in association with rituximab were discontinued in five patients at the end of follow-up. None of the patients experienced visual worsening during the follow-up. No drug-related complications were encountered. CONCLUSIONS: Rituximab may be a promising effective treatment option for refractory uveitis associated with JIA leading to long-term quiescence of uveitis, particularly for patients who have not previously responded to other biologic therapies.

Photosensitizers and Photodynamic Therapy: Verteporfin.

Photodynamic therapy (PDT) is a phototherapy in which a photosensitive dye is injected into a peripheral vein and activated by light in order to occlude choroidal vessels or change their permeability. PDT has been largely applied in the treatment of choroidal neovascularization (CNV), especially CNV related to age-related macular degeneration, but was also of benefit in other diseases, including central serous chorioretinopathy and choroidal hemangioma.

Retinal Hereditary and Degenerative/Dystrophic Diseases (Non-Age-Related Macular Degeneration).

The definition of hereditary retinal diseases includes heterogeneous conditions leading to significant visual impairment. Great strides are being made in the management of many of these dystrophies, with many ongoing trials aiming to ascertain if a pharmacological therapy can reverse or at least stop the natural course of these disorders. In addition, good results have also been achieved in the treatment of typical complications of inherited dystrophies such as cystoid macular edema and choroidal neovascularization.

Tear osmolarity in ocular graft-versus-host disease.

PURPOSE: The aim of this study was to evaluate tear osmolarity in patients with chronic graft-versus-host disease (cGVHD) with ocular involvement. METHODS: In this observational cross-sectional study of 56 patients with ocular cGVHD referred to the tertiary-care Ocular Immunology and Uveitis Service at the San Raffaele Scientific Institute, Milan, from May 2010 to November 2013, we evaluated the following clinical parameters: Ocular Surface Disease Index (OSDI) symptoms questionnaire, tear osmolarity, Schirmer test, tear film break-up time (TBUT), corneal and conjunctival staining. RESULTS: All patients developed systemic GVHD after undergoing allogeneic hematologic stem cell transplantation. Mean osmolarity was 314.0 ± 22.1 mOsm/L, mean OSDI score was 26.4 ± 21.2, mean TBUT was 6.50 ± 4.75 seconds, and mean Schirmer test value was 3.8 ± 3.3 mm. Tear osmolarity significantly inversely correlated with TBUT (r = 0.681; P < 0.001). Statistically significant inverse correlation was present with the Schirmer test (r = 0.203; P < 0.001), and positive correlation with the OSDI score (r = 0.188; P < 0.001), but both with low correlation strength. Osmolarity was statistically different in the subgroups according to the Oxford corneal staining scale (P = 0.0006) and to the van Bijsterveld conjunctival staining score (P = 0.006). CONCLUSIONS: Tear osmolarity increased in patients with ocular cGVHD, significantly correlated with TBUT and, to a lesser extent, with the Schirmer test value and OSDI. These results emphasize the role of aqueous-deficient and evaporative dry eye disease in patients with cGVHD after undergoing allogeneic hematologic stem cell transplantation. Tear osmolarity may be considered a useful test in diagnostic assessment of dry eye disease associated with cGVHD.

Tear film osmolarity in ocular mucous membrane pemphigoid.

PURPOSE: The aim of this study was to evaluate tear film osmolarity in patients with ocular mucous membrane pemphigoid (MMP). METHODS: This observational cross-sectional study included 40 patients with biopsy-proven ocular MMP at Foster stage III referred to the tertiary-care Ocular Immunology and Uveitis Service at the San Raffaele Scientific Institute in Milan from June 2010 to August 2013. We evaluated the following clinical parameters: tear film osmolarity, ocular surface disease symptoms (OSDI) questionnaire, Schirmer test, tear film break-up time (TFBUT), and corneal and conjunctival staining. RESULTS: Forty patients (27 women and 13 men) were enrolled. All patients were undergoing systemic immunosuppressive therapy: 19 patients (47.5%) were on methotrexate, 9 (22.5%) were on mycophenolate mofetil, 9 (22.5%) were on low-dose corticosteroids, and 3 (7.5%) were on azathioprine. The mean osmolarity was 322.90 ± 33.39 mOsm/L, the mean OSDI score was 73.2 ± 17.9, the mean TFBUT was 6.60 ± 3.13 seconds, and the mean Schirmer test value was 4.07 ± 3.58 seconds. Tear film osmolarity significantly correlated with the TFBUT (r = 0.80; P < 0.0001), whereas no clinical correlation was found with the Schirmer test value (r = 0.01; P = 0.40) or with the OSDI score (r = 0.02; P = 0.29). Osmolarity did not turn out to be statistically different in the subgroups according to the Oxford corneal staining scale (P = 0.71) and to the Van Bijsterveld conjunctival staining score (P = 0.31). CONCLUSIONS: Tear osmolarity increased in patients with ocular MMP and correlated with the TFBUT. This result emphasizes the role of evaporative dry-eye condition in patients with ocular MMP. Tear osmolarity may be considered as a useful test in the diagnostic assessment of dry eye associated with MMP and for targeting therapeutic decisions.

Clinical features of patients with episcleritis and scleritis in an Italian tertiary care referral center.

PURPOSE: To evaluate demographic characteristics, clinical features, systemic disease associations, visual outcomes, and treatment modalities of patients with episcleritis and scleritis in an Italian tertiary care referral center. METHODS: Data from 25 patients with episcleritis and from 85 patients with scleritis followed from 2003 to 2012 were retrospectively evaluated. The main outcome measures were demographics, ocular disease characteristics, presence of systemic associated disease, treatment regimen, and follow-up period. RESULTS: Episcleritis and scleritis were found bilaterally in 24% and 31% of patients, respectively (p<0.521). The episcleritis was diffuse in 15 and focal in 10 patients, while the scleritis was diffuse in 49, nodular in 28, necrotizing in 6, and posterior in 2 patients. Anterior uveitis (4% vs 31%; p<0.006), peripheral ulcerative keratitis (0% vs 14%; p<0.167), ocular hypertension (0% vs 7%; p<0.333), and a decrease in visual acuity (4% vs 19%; p<0.112) were encountered as ocular complications in patients with episcleritis and patients with scleritis, respectively. An associated systemic disease was found in 20% and 52% of patients with episcleritis and patients with scleritis (p<0.004). Among patients with episcleritis, 76% required topical corticosteroid treatment to achieve disease resolution, 16% oral nonsteroidal anti-inflammatory drugs (NSAIDs), and 8% antivirals; 39% of patients with scleritis required systemic NSAIDs, 12% oral corticosteroids, 34% immunosuppressive drugs, and 15% antibiotics or antivirals. CONCLUSIONS: The importance of differentiating scleritis from episcleritis is remarkable given the significant difference in the degree of ocular complications and associated systemic diseases between these ocular conditions. Prompt diagnosis, systemic assessment, and treatment are fundamental in all patients with scleral inflammation.

Intravitreal bevacizumab for nonsubfoveal choroidal neovascularization associated with angioid streaks.

PURPOSE: To evaluate the effects of intravitreal bevacizumab injections in the treatment of nonsubfoveal choroidal neovascularization (CNV) associated with angioid streaks. DESIGN: Nonrandomized, interventional, prospective case series. METHODS: Fifteen patients (15 eyes) affected by juxtafoveal or extrafoveal CNV secondary to angioid streaks were enrolled in the study. All patients underwent a complete ophthalmologic examination, including best-corrected visual acuity (BCVA) measurement on Early Treatment Diabetic Retinopathy Study (ETDRS) chart, optical coherence tomography (OCT), and fluorescein angiography (FA). The protocol treatment included a first injection, followed by repeated injections over a 12-month follow-up period on the basis of the detection of new hemorrhage on biomicroscopic examination, any type of fluid on OCT, or presence of leakage on FA. PRIMARY OUTCOME MEASURES: Mean changes in BCVA and proportion of eyes gaining at least 10 letters (2 ETDRS lines) at the end of the follow-up. SECONDARY OUTCOMES: Mean changes of central macular thickness (CMT) and extension to the fovea. RESULTS: Mean BCVA did not change throughout the follow-up period, being 0.2 ± 0.2 logMAR at baseline and 0.2 ± 0.3 logMAR at the 12-month examination. A functional improvement of at least 2 ETDRS lines was achieved by 5 eyes (33%), with 3 eyes (20%) gaining 3 lines. Mean CMT at baseline was 215 ± 13 µm and 225 ± 85 µm at the 12-month examination. Two eyes (13.3%) showed CNV extension to the fovea. CONCLUSIONS: Intravitreal bevacizumab injection can be a beneficial approach for the management of nonsubfoveal CNV secondary to angioid streaks over a 1-year follow-up.

Clinical application of an in-house ELISPOT assay in patients with suspicious tuberculous uveitis and no signs of active tuberculosis.

PURPOSE: The purpose of this study is to evaluate the rate of Mycobacterium tuberculosis infection in uveitis patients using an ELISPOT-IFN-gamma (ELISPOT-MTP) assay and a tuberculin skin test (TST). METHODS: Fifty-three patients with suspicious tuberculous uveitis, seen at the Ocular Immunology and Uveitis Service, Scientific Institute San Raffaele, Milan, Italy, were compared with 233 healthy control subjects. All uveitis patients, together with healthy control subjects, underwent in-house ELISPOT-MTP assay and then the TST. RESULTS: None of the patients had signs of active tuberculosis. A total of 75.5% of uveitis patients showed positive TST reaction while 58.5% responded positively to ELISPOT-MTP. In healthy individuals, these responses were 30.5% and 25.3%, respectively (p<0.0001). In a different diagnosis subset, TST and ELISPOT positivity were, respectively, 80% and 50% in anterior uveitis; 75% and 50% in intermediate uveitis; 100% and 87.5% in serpiginous-like choroiditis; 90% and 80% in posterior uveitis; and 57.1% and 42.9% in panuveitis. Serpiginous-like choroiditis and posterior uveitis patients had a higher number of ELISPOT-MTP positive results and a higher grade of intensity of ELISPOT-MTP responses compared to healthy control subjects (p=0.0098). CONCLUSIONS: Our uveitis patients had higher M tuberculosis infection rate and grade of intensity response than healthy control subjects detected by ELISPOT-MTP. This response is statistically significant and higher in patients with serpiginous-like choroiditis and posterior uveitis.