Bianka Sobolewska

Treatment of ocular rosacea with once-daily low-dose doxycycline.

Purpose: The aim of this study was to determine the efficacy of once-daily systemic treatment of ocular rosacea with a slow-release form of 40 mg of doxycycline. Methods: Fifteen patients with ocular rosacea were enrolled between February 2010 and October 2012 in a retrospective observational case series. Patient complaints and clinical findings including blepharitis with telangiectasia and meibomian gland dysfunction, conjunctival redness, and fluorescein staining of the cornea were evaluated. The ocular manifestations were scored as follows: 0—absent, 1—mild, 2—moderate, and 3—severe. All measurements were repeated at the 6-week follow-up visit. The mean duration of treatment was 8 months (range, 5–12 months), and the mean duration of the follow-up was 9 months (range, 6–17 months). Results: At the baseline visit, 73.3% of the patients had severe complaints, and 80% had severe blepharitis despite topical therapy with artificial tears and eyelid hygiene. After 12 weeks of systemic therapy, severe complaints and blepharitis strongly improved and were seen in only 13.3% and 20% of the patients (P = 0.01). Follow-up investigations 6 to 17 months after discontinuation of the treatment showed further significant improvement of complaints (absent or mild in 66.7% and 20% of the patients, respectively) and blepharitis (absent or mild in 26.7% and 60% of the patients, respectively). One patient had a mild stomach ache so that therapy was shortened to 5 months. Conclusions: An antiinflammatory dose of slow-release doxycycline 40 mg given daily may be an effective and safe therapy of ocular rosacea.

Treatment Strategies in Primary Vitreoretinal Lymphoma: A 17-Center European Collaborative Study

IMPORTANCE The best treatment option for primary vitreoretinal lymphoma (PVRL) without signs of central nervous system lymphoma (CNSL) involvement determined on magnetic resonance imaging or in cerebrospinal fluid is unknown. OBJECTIVE To evaluate the outcomes of treatment regimens used for PVRL in the prevention of subsequent CNSL. DESIGN, SETTING, AND PARTICIPANTS A retrospective cohort study was conducted at 17 referral ophthalmologic centers in Europe. We reviewed clinical, laboratory, and imaging data on 78 patients with PVRL who did not have CNSL on presentation between January 1, 1991, and December 31, 2012, with a focus on the incidence of CNS manifestations during the follow-up period. INTERVENTIONS The term extensive treatment was used for various combinations of systemic and intrathecal chemotherapy, whole-brain radiotherapy, and peripheral blood stem cell transplantation. Therapy to prevent CNSL included ocular radiotherapy and/or ocular chemotherapy (group A, 31 patients), extensive systemic treatment (group B, 21 patients), and a combination of ocular and extensive treatment (group C, 23 patients); 3 patients did not receive treatment. A total of 40 patients received systemic chemotherapy. MAIN OUTCOMES AND MEASURES Development of CNSL following the diagnosis of PVRL relative to the use or nonuse of systemic chemotherapy and other treatment regimens. RESULTS Overall, CNSL developed in 28 of 78 patients (36%) at a median follow-up of 49 months. Specifically, CNSL developed in 10 of 31 (32%) in group A, 9 of 21 (43%) in group B, and 9 of 23 (39%) in group C. The 5-year cumulative survival rate was lower in patients with CNSL (35% [95% CI, 50% to 86%]) than in patients without CNSL (68% [95% CI, 19% to 51%]; P = .003) and was similar among all treatment groups (P = .10). Adverse systemic effects occurred in 9 of 40 (23%) patients receiving systemic chemotherapy; the most common of these effects was acute renal failure. CONCLUSIONS AND RELEVANCE In the present series of patients with isolated PVRL, the use of systemic chemotherapy was not proven to prevent CNSL and was associated with more severe adverse effects compared with local treatment.

Tocilizumab in Uveitic Macular Edema Refractory to Previous Immunomodulatory Treatment

ABSTRACT Purpose: To analyze the efficacy of tocilizumab in uveitic macular edema (ME) resistant to various immunomodulatory drugs. Methods: Patients received tocilizumab every 4 weeks intravenously. Central foveal thickness (CFT) was assessed by optical coherence tomography (OCT). Results: Five patients (8 eyes) who were ineffectively pretreated with systemic prednisolone, at least one immunosuppressive drug, and at least one biologic drug for uveitic macular edema were included in the study. At 3 months, a response of ME (≥25% reduction in CFT) was observed in 6 eyes (75.0%) of 5 patients. During follow-up, complete resolution of ME was achieved in 5 eyes (62.5%) of 4 patients. Improvement of BCVA was observed in 3 eyes of 3 patients, and stabilization in 3 eyes of 3 patients. Tocilizumab was well tolerated, and no severe side effects occurred. Conclusions: Treatment with tocilizumab can be considered in chronic uveitic macular edema even if previous immunomodulatory therapy has failed.

Therapeutic Efficacy of Bevacizumab for Age-Related Macular Degeneration

CATT (Comparison of Age-related macular degeneration [AMD] Treatment Trials) examined the efficacy of ranibizumab and bevacizumab for the treatment of neovascular AMD. This prospective, randomized, but unblinded trial revealed a significant improvement in vision with both treatments in terms of visual acuity; importantly, patients with juxtafoveal choroidal neovascularization (CNV) and retinal pigment epithelial detachments were not excluded from the study. Monthly treatment with the drugs resulted in similar increases in visual acuity, although angiograms indicated that ranibizumab was superior in terms of reducing retinal fluid and leakage.As the study also differentiated between a fixed regimen and an as-needed (pro re nata [PRN]) dosing regimen, a larger sample size and Bonferroni statistical correction were necessary. The equivalence of the PRN dosing of bevacizumab to the monthly treatment could not be confirmed. Almost all of the frequent deviations from the protocol (referring to retreatment criteria: 25.7–28.5%) resulted in under-treatment. Since this applied to both drugs equally, under-treatment alone could not explain the larger loss of visual acuity observed in the bevacizumab PRN arm. The PRN regimen was generally associated with a larger lesion size after 12 months compared with the fixed treatment regimens.The investigators accepted the drawbacks of an incomplete masking to allow co-payment by Medicare. As assessments of drug trials are often politically motivated, the higher demands of a non-inferiority trial compared with a superiority design must be emphasized. A comparison of the per-protocol and last-observation-carried-forward analysis has not yet been published; ongoing subgroup analysis might highlight the impact of different lesion characteristics. While CATT provided further evidence for the efficacy of bevacizumab treatment, differences in adverse events between the two treatments (e.g. a higher rate of serious adverse events with bevacizumab compared with ranibizumab) were reported; however, these still have to be analysed, with the larger sample sizes of previous ranibizumab studies needing to be taken into account. Preclinical studies imply some differences between the drugs in terms of their adverse event profiles. A possible increased risk of adverse events could not be ruled out by previous clinical case series and CATT because the sample sizes and the follow-up intervals were not adequate.The large discrepancy in the price of bevacizumab versus ranibizumab in the US means a cost-benefit analysis is warranted. A lack of quality-of-life data has prevented calculation of an appropriate bevacizumab price in the context of its performance in the ophthalmological setting.Thus, CATT suggests that a favourable visual acuity might be achieved by very frequent administration of bevacizumab in patients with neovascular AMD. Although there are certain safety caveats, increased focus on subgroup analyses and obtaining longer follow-up data are expected to yield additional information of clinical relevance.

Different Effects of Ranibizumab and Bevacizumab on Platelet Activation Profile

Purpose: The aim of the study was to evaluate the potential influence of ranibizumab and bevacizumab on platelet activation and aggregation, which are critical processes in the pathogenesis of arterial thromboembolic events (ATEs). Methods: For the assessment of platelet function, flow cytometry and aggregometry were employed. Platelets were isolated from healthy volunteers and exposed to ranibizumab (1 mg/ml and 150 ng/ml) and bevacizumab (2.5 mg/ml and 3 μg/ml) or their solvents for 10 and 30 min prior to the addition of TRAP (25 μM), PAR-4-AP (25 μM) or thrombin (0.02 U/ml). The surface expression of activated GP IIb/IIIa, P-selectin (CD62P) and platelet-bound stromal cell-derived factor-1 (SDF-1) was measured on resting (nonactivated) and activated platelets by flow cytometry. The platelet aggregation capacity was examined using light transmission aggregometry. Results: The expression of surface activation markers did not differ significantly between nonstimulated and TRAP-, PAR-4-AP- or thrombin-activated platelets after incubating with ranibizumab. However, GP IIb/IIIa, CD62P and SDF-1 were significantly downregulated in PAR-4-AP- and thrombin-activated platelets after exposure to bevacizumab 2.5 mg/ml. In addition, ranibizumab- and bevacizumab-FITC were significantly increased in all activated platelets. No significant differences were observed in the aggregation of activated platelets after incubation with ranibizumab or bevacizumab. Conclusion: All ranibizumab concentrations as well as the bevacizumab concentration of 3 μg/ml had no influence on platelet activation and aggregation. Therefore, this in vitro study did not show any relationship between the exposition of activated platelets to ranibizumab or bevacizumab and the development of ATEs. However, the highest level of bevacizumab interfered with platelet activation, leading to downregulation of platelet activation markers. This observation might explain why the systemic treatment with high-dose bevacizumab could be associated with an increased risk of bleeding. Regarding the use of lower intravitreal dosages, further research should focus on the complex interactions between platelets and other cells, such as endothelial cells, which might stronger relate to a potentially increased risk of ATEs and depend on systemic vascular endothelial growth factor levels. Facing the different activation profiles, the diverse effects of the drugs on the cellular level have to be critically scrutinized for their clinical relevance.

Long-term visual outcome and its predictive factors following treatment of acute submacular hemorrhage with intravitreous injection of tissue plasminogen factor and gas.

PURPOSE To investigate the long-term functional outcome and its predictive factors of treatment of acute submacular hemorrhage secondary to age-related macular degeneration with intravitreal application of recombinant tissue plasminogen activator (rt-PA) and gas. METHODS Twenty-six patients were enrolled in the retrospective case series. A complete history and ocular examination, including fluorescein angiography, were performed. The best-corrected visual acuity was measured with a Snellen chart. Patients were followed up for 12 to 131 months (mean: 49 months). All patients underwent intravitreal injection of rt-PA (50 μg) and expansile gas. Primary outcome measures were best postoperative and final visual acuity and degree of blood displacement. RESULTS The size of the subretinal hemorrhage ranged from 0.5 to 28 disc diameters, and the degree of blood displacement was defined as complete (≥1 disc area from the center of the fovea), partial, or no displacement. Twenty-one (81%) patients showed partial or complete displacement of hemorrhage. Due to lack of displacement of hemorrhage in 5 patients (19%), submacular surgery was performed. In 13 of 21 (62%; P=0.0001) patients with displacement of hemorrhage, the best postoperative visual acuity improved ≥2 lines. The final visual acuity improved ≥2 lines in 42.9% (9 of 21), was stable in 23.8% (5 of 21), and worse ≥2 lines in 33.3% (7 of 21) of patients. The short duration of hemorrhage (≤4 days) and complete displacement of blood, independent of the hemorrhage size, were significantly associated with better postoperative visual acuity (P=0.0001, P=0.0001, respectively). CONCLUSION Intravitreal injection of rt-PA and gas seem to be more effective when applied within the first 4 days of acute submacular hemorrhage. Preoperative visual acuity as well as displacement of hemorrhage might be useful to predict final visual acuity.

Antiproliferative and cytotoxic properties of moxifloxacin on rat retinal ganglion cells.

Abstract Purpose: To evaluate the antiproliferative and cytotoxic properties of moxifloxacin on cultured rat retinal ganglion cells (RGC5). Materials and Methods: Rat retinal ganglion cells were exposed to various concentration of moxifloxacin (5–1500 μg/mL). For antiproliferative properties, the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) test was performed. Cellular cytotoxicity was assessed by using the Live/Dead viability/cytotoxicity assay and analyzed by fluorescence microscopy after 24 and 72 h of incubation, respectively. Results: Neither cytotoxic nor antiproliferative effect of moxifloxacin was observed below 50 μg/mL on RGC5 cells after 24 and 72 h of incubation. At higher concentrations of moxifloxacin (150 μg/mL, 500 μg/mL, and 1500 μg/mL (p < 0.001)) the number of viable cells and the proliferation rate of RGC5 were significantly reduced. Conclusions: These results suggest a dose-dependent cytotoxic and antiproliferative effect of moxifloxacin on RGC5. Therefore, intracameral application of moxifloxacin should be used cautiously in patients with increased risk of retinal ganglion cells damage, particularly in glaucoma patients.

Mycophenolate sodium for the treatment of chronic non-infectious uveitis of childhood

Aim To assess the efficacy and tolerability of mycophenolate sodium (MPS) in the therapy of children with chronic non-infectious uveitis. Methods Retrospective analysis of 23 children with chronic uveitis, treated with MPS, with a follow-up of at least 6 months. The main outcome measures were time to uveitis reactivation and corticosteroid-sparing effect under MPS treatment. The secondary outcome measures were best-corrected visual acuity (BCVA) and treatment-related side effects. Results From 23 patients included in the study, 2 patients had anterior uveitis, 19 had intermediate uveitis and 2 had panuveitis. The probability of reactivation-free survival after MPS initiation was estimated as 65% at both 1 and 2 years. The probability of discontinuing systemic corticosteroids after 1 year of treatment was 39% and after 2 years 51%. The probability to taper corticosteroids to a daily dosage of ≤0.1 mg/kg after 1 and 2 years was 62% and 85%, respectively. BCVA improved or remained stable in 96% of eyes after 1 year of therapy. Treatment-related side effects were found in nine children (rate: 0.17/patient-year). No therapy discontinuation because of side effects was needed. Conclusion Our data suggest that MPS is useful and well tolerated in children with chronic uveitis. MPS seems to be an effective drug for the treatment of chronic non-infectious uveitis of childhood and may be preferred as a first-line steroid-sparing agent in this form of uveitis.

Cytotoxic Effect of Voriconazole on Human Corneal Epithelial Cells.

Background: To assess the cytotoxic properties of voriconazole and sulfobutylether-β-cyclodextrin (SBECD) on cultured primary human corneal epithelial cells. Methods: Human corneal epithelial cells were cultured and exposed to various concentrations of SBECD (0.016-32 mg/ml) and voriconazole (0.001-2 mg/ml). Cellular cytotoxicity of SBECD and voriconazole on human corneal epithelial cells was evaluated using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide test and the LIVE/DEAD Viability/Cytotoxicity Assay with fluorescence microscopy analysis. Cell damage was assessed with phase-contrast microscopy after 24 h of exposure to SBECD and voriconazole. Results: The cytotoxicity tests and the morphological characteristic demonstrated the dose-dependent toxic effect of SBECD and voriconazole on human corneal epithelial cells. No corneal epithelial cytotoxicity was observed below the concentration of 0.08 and 0.025 mg/ml after 24-hour exposure to SBECD and voriconazole, respectively. Conclusions: The results of the study reveal the dose-dependent cytotoxic effect of SBECD and voriconazole on cultured human corneal epithelial cells. Therefore, voriconazole eye drops should be used cautiously in the treatment of fungal corneal ulcers.

Long-term Follow-up of Patients with Tubulointerstitial Nephritis and Uveitis (TINU) Syndrome

ABSTRACT Purpose: To evaluate the response to treatment in patients with tubulointerstitial nephritis and uveitis (TINU) syndrome over a long-term follow-up period. Methods: Nine patients with TINU syndrome were retrospectively reviewed. The mean follow-up was 54.8 months (range: 24–133 months). Results: The mean number of recurrences per year declined from 1.7 in the 1st year to 0.66 in the 2nd year of treatment. The ocular inflammation responded to local corticosteroids in two patients, systemic corticosteroids in two patients, immunosuppressive therapy in four patients, and anti-TNF-α blocking agent in one patient. The therapy could be discontinued in six (67%) patients after a mean treatment period of 29.5 months. In five patients, remission with the recurrence-free period of 12.8 months was achieved. Conclusions: TINU syndrome was characterized by limited responsiveness to corticosteroid therapy and less by severe complications. A long-term course of immunosuppressants or biologics was necessary to control the uveitis and led to induction of remission.