Luigi Berchicci

Evidence for Anti-VEGF Treatment of Diabetic Macular Edema

Diabetic macular edema (DME) is the most important cause of vision loss in patients with diabetes mellitus. Diabetic retinopathy has a remarkable impact on public health and on the quality of life of diabetic patients and thus requires special consideration. The first line of treatment remains the management of systemic risk factors but is often insufficient in controlling DME and currently, laser retinal photocoagulation is considered the standard of care. However, laser treatment reduces the risk of moderate visual loss by approximately 50% without guaranteeing remarkable effects on visual improvement. For these reasons, new strategies in the treatment of DME have been studied, in particular the use of anti-vascular endothelial growth factor (anti-VEGF) drugs. VEGF is a pluripotent growth factor that acts as a vasopermeability factor and an endothelial cell mitogen. For this reason, it represents an interesting candidate as a therapeutic target for the treatment of DME. The aim of this article is to review the evidence behind the use of anti-VEGF drugs in the treatment of DME.

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.

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 (r2 = 0.681; P < 0.001). Statistically significant inverse correlation was present with the Schirmer test (r2 = 0.203; P < 0.001), and positive correlation with the OSDI score (r2 = 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.

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.

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 (r2 = 0.80; P < 0.0001), whereas no clinical correlation was found with the Schirmer test value (r2 = 0.01; P = 0.40) or with the OSDI score (r2 = 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 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-γ (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.

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.

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.

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.