Immunomodulatory therapy in ophthalmology - is there a place for topical application?

Topical corticosteroids, although effective in the treatment of ocular immune-mediated diseases, are well known for their ocular side-effects. Not surprisingly, a variety of alternative immunomodulatory agents have been tested for topical use including cyclosporin A (CsA), mycophenolate mofetil (MMF), tacrolimus (FK506), rapamycin (sirolimus) and leflunomide. Local application bears the possibility to avoid the severe side-effects of systemic therapy. The effect of topical therapy is naturally restricted to local immune response mechanisms, such as antigen presentation by Langerhans and dendritic cells. Moreover, many immunomodulatory agents (e.g. CsA) are lipophilic and thus have low water solubility and penetrate insufficiently intra-ocularly, often being stored in the lipophilic corneal epithelial barrier. Therefore, the therapeutical success is limited for intra-ocular immune-mediated diseases like anterior uveitis. However, a multitude of strategies have been introduced to circumvent these problems including complexing substances such as cyclodextrins (CDs) and liposomes. In the prevention and treatment of transplant rejection after keratoplasty, many attempts to introduce topical immunomodulatory therapy have failed; on the other hand, further therapeutic options not primarily expected are being evaluated today such as treatment of severe keratoconjunctivitis sicca. In our own studies, we investigated the pharmacokinetics of topical treatment with different agents including MMF and evaluated the efficacy of topical treatment in animal models for uveitis and keratoplasty. Taken together, topical immunomodulatory therapy will not replace systemic therapy but further treatment options can be expected.     

The role of serum lipids in exudative diabetic maculopathy: is there a place for lipid lowering therapy?

Diabetic maculopathy is a common complication of diabetes mellitus, characterised by macular oedema and frequently accompanied by lipid exudation. It is the major cause of loss of vision from diabetic retinopathy. There is some evidence to implicate serum lipids in exudative maculopathy; cross-sectional studies suggest that higher serum lipid levels are found in patients with macular exudates, and prospective studies have shown an increased risk of exudative maculopathy if baseline cholesterol is higher.The treatment for diabetic maculopathy is laser photocoagulation of the pigment epithelium. With the advent of systemic lipid lowering therapy over the last decade, there may be potential for medical therapy also. There is some anecdotal evidence of the effect of lipid lowering agents (particularly statins) in reducing exudate, and a number of studies have shown that lipid lowering therapy may reduce macular exudates, but numbers in these trials are small. A randomised controlled trial is now required to investigate whether the use of systemic lipid lowering therapy is of benefit in patients with exudative maculopathy, even in the absence of dyslipidaemia.     

Is there a delay in bathing the external eye in the treatment of ammonia eye burns? Comparison of two ophthalmic solutions: physiological serum and Diphotérine

PURPOSE: An experimental animal study was conducted to analyze the delay for ocular bathing in the treatment of severe ocular ammonia burns. Two solutions of ocular wash, saline solution and Diphotérine were compared. MATERIAL: and methods: The study included 23 eyes of New Zealand albino rabbits that received for 1 minute 100 microl of 15.3% ammonium solution. Each eye was then washed with 250 of saline solution or 250ml Diphotérine after a delay of 1, 3, 5, 10 or 30 minutes. Effects were assessed on the basis of changes in anterior chamber pH, ammonia concentration in the anterior chamber, and cytopathology examination of the burned corneas. RESULTS: Ocular wash with Diphotérine in the first minutes following ocular burn induced an inflexion of the pH curve unlike ocular wash with saline solution. At 30 minutes, there was no inflexion of the pH curve and the ammonia concentration in the anterior chamber was low. Contrary to ocular wash using Diphotérine, stromal edema was seen at cytopathological analysis after washing with saline solution. CONCLUSIONS: This study provides evidence of the interest of ocular bathing in the first minutes following ocular burn by ammonia. The efficacy of external ocular washing with Diphotérine was proven by biochemical and cytopathological demonstrations. The importance of sequelae were related to the degree of initial stromal edema.     

Model study of AREDS antioxidant supplementation of AMD compared to Visudyne: a dominant strategy?

OBJECTIVES: In Ontario, Canada, in a cohort of all people initially aged 50-54 years, modeling whether the Age-Related Eye Disease Study (AREDS) antioxidant supplementation for stage 3 and 4 AMD would decrease the costs of photodynamic treatment with Visudyne. PERSPECTIVE: Third party payer, the Ontario Health Insurance Plan. METHODS: Using reported risk reductions, prevalence data by age and sex from the Beaver Dam studies, and yearly costs: AREDS 182.50 Canadian dollars, potential savings were calculated as the difference or incremental cost between the estimated medical costs for the untreated cohort of 17,000 Canadian dollars for Visudyne treatment of individuals with neovascularization and the same cohort if stage 3 and 4 AMD patients were treated with antioxidants, decreasing progression to neovascularization. Different scenarios were explored for sensitivity analysis of direct cost savings. RESULTS: For the Ontario cohort of approximately 788,000 aged 51-55 years in 2001, for photodynamic therapy of the untreated cohort, modeled costs were 1.7 billion Canadian dollars. AREDS treatment costs would be 513 million Canadian dollars. AREDS would reduce photodynamic therapy costs, a net saving of 431 million Canadian dollars, a saving of 547 Canadian dollars per person in the total cohort, or 6,753 Canadian dollars per stage 3 and 4 patient treated. To explore the sensitivity of this model to AMD incidence rather than prevalence data, Framingham incidence data were incorporated in the model: net savings of 70.3 million Canadian dollars were modeled using Framingham incidence data. CONCLUSION: Under reasonable assumptions, if the case progresses to wet AMD (1) AREDS with Visudyne is less expensive than Visudyne alone in every five-year time period for the cohort that is age 50-54 right now until they become 75-79; thus, the lifetime cost is lower; (2) AREDS with Visudyne yields more QALYs than Visudyne alone in every five-year interval; (3) under all but the most extreme assumptions, the conclusions reached are robust. Even when AREDS costs a little more, it yields more QALYs at a reasonable cost per QALY. Thus, AREDS antioxidant supplementation appears to be a dominant strategy for macular degeneration. Applied to the whole Canadian population, the potential medical cost savings for Visudyne treatment of neovascular AMD are 5.6 billion Canadian dollars in direct costs. These values would be tenfold higher for the USA, because of the currency and population size differences.     

Macular ischaemia: a contraindication for anti-VEGF treatment in retinal vascular disease?

Anti-vascular endothelial growth factor (anti-VEGF) therapy has been shown to be effective at improving vision in patients with macular oedema due to diabetic retinopathy and vein occlusions, but blocking VEGF at least in theory could be detrimental to vascular integrity. For this reason, some patients with macular ischaemia were excluded from studies showing the effectiveness of therapy. A considerable number of patients present with mixed pathology of macular oedema and macular ischaemia and it is often impossible to determine the degree to which ischaemia accounts for decreased vision. In this review, the authors have dealt with the specific question of whether or not there is evidence to support potential worsening of the macular perfusion and visual function after anti-VEGF treatment with bevacizumab or ranibizumab for macular oedema secondary to diabetic retinopathy or retinal vein occlusions, especially if there is coexisting macular ischaemia. The authors conclude that anti-VEGF therapy rarely seems to further compromise the retinal circulation; however, worsening of macular ischaemia in the long term cannot be definitely excluded, particularly in eyes with significant ischaemia at baseline and after repeated intraocular anti-VEGF injections. The decision to offer prolonged anti-VEGF treatment in cases of significant coexisting macular ischaemia should not be based only on measurements of macular thickness; instead repeat fluorescein angiograms should be performed.     

Does cardiovascular therapy affect the onset and recurrence of preretinal and vitreous haemorrhage in diabetic eye disease?

AIMS: To review the role of cardiovascular disease and therapy in the onset and recurrence of preretinal/vitreous haemorrhage in diabetic patients. METHODS: Retrospective case note analysis of diabetic patients with vitreous haemorrhage from the Diabetic Eye Clinic at Birmingham Heartlands Hospital. RESULTS: In total, 54 patients (mean age 57.1, 37 males, 20 type I vs 34 type II diabetic patients) were included. The mean (SD) duration of diagnosed diabetes at first vitreous haemorrhage was significantly longer, 21.9 (7.6) years for type I and 14.8 (9.3) years for type II diabetic patients (P < 0.01, unpaired t-test, two-tailed).Aspirin administration was not associated with a significantly later onset of vitreous haemorrhage. Four episodes were associated with ACE-inhibitor cough. There was a trend towards HMGCoA reductase inhibitor (statin) use being associated with a delayed onset of vitreous haemorrhage: 21.4 years until vitreous haemorrhage (treatment group) vs 16.2 years (nontreatment group) (P = 0.09, two-tailed, unpaired t-test, not statistically significant). During follow-up 56 recurrences occurred, making a total of 110 episodes of vitreous haemorrhage in 79 eyes of 54 patients. The mean (range) follow-up post haemorrhage was 1067 (77-3842) days, with an average of 1.02 recurrences. Age, gender, diabetes type (I or II) or control, presence of hypertension or hypercholesterolaemia, and macrovascular complications were not associated with a significant effect on the 1-year recurrence rate. Aspirin (and other antiplatelet or anticoagulant agents) and ACE- inhibitors appeared to neither increase nor decrease the 1-year recurrence rate. However, statin use was significantly associated with a reduction in recurrence (Fisher exact P < 0.05; two-tailed) with an odds ratio (95% CI) of 0.25 (0.1-0.95). CONCLUSION: In this retrospective analysis, the onset of preretinal/vitreous haemorrhage was not found to be accelerated by gender, hypertension, hypercholesterolaemia, evidence of macrovascular disease, or HbA1c. Neither aspirin nor ACE-inhibitor administration accelerated the onset or recurrence of first vitreous haemorrhage. Statins may have a protective role, both delaying and reducing the recurrence of haemorrhage.     

Is homelessness a risk factor for eye disease? Results of a German screening study

BACKGROUND: There is general agreement on the presence of a correlation between poverty and impaired health. However, only scarce data are available on whether this also applies to the incidence of eye disease. The present study was carried out to evaluate the prevalence of ocular disease in homeless people in Germany. METHODS: 107 homeless people (97 male, 10 female; mean age 49 years, range 18-81 years) treated in specialised social service institutions were investigated prospectively according to a standardised ophthalmological screening protocol. This comprised visual acuity, assessment of pupillary light reaction, intra-ocular pressure, slit lamp examination as well as funduscopy. RESULTS: The median best-corrected visual acuity of all 213 eyes examined was 0.8 (range: no light perception to 1.25). 74 eyes of a subgroup of 50 patients showed one or more of the following disorders: 32% of the patients suffered from external eye disease, 8% exhibited a cataract associated with a visual acuity of 0.63 or below. 6% of the patients had optic nerve atrophy, and 4% suffered from amblyopia. Diabetic retinopathy as well as age-related macular degeneration were detected in 2%, while anophthalmos, lid malposition and traumatic choroidal rupture were noted in 1% of patients. The median visual acuity measured in these 74 eyes was 0.5 (range: no light perception to 1.25), which differs significantly from the acuity of 0.8 in the entire study population (p < 0.001). The prevalence of legal blindness according to WHO criteria was 2%. CONCLUSIONS: The present study revealed an unexpectedly high prevalence of optic nerve atrophy in homeless people. The prevalence for cataract and legal blindness was slightly higher than in representative epidemiological investigations. Thus, homelessness seems to be correlated with an increased ocular morbidity. As best-corrected visual acuity differed significantly between eyes with and those without eye disease, the assessment of this parameter may serve as a cost-effective first-stage screening method.     

Sodium hyaluronate eye drops of different osmolarity for the treatment of dry eye in Sjögren's syndrome patients

AIM: To study the effect of the treatment of dry eye in Sj?gren's syndrome patients with hypotonic or isotonic hyaluronate eye drops. METHODS: 40 Sj?gren's syndrome patients were divided in two groups and treated as follows: group 1 with hypotonic (150 mOsm/l) 0.4% hyaluronate eye drops; group 2 with isotonic 0.4% hyaluronate eye drops. The eye drops were instilled six times a day for 90 days. Grading of subjective symptoms, break up time (BUT), corneal fluorescein staining, conjunctival rose bengal staining, Schirmer's I test, and conjunctival impression cytology were carried out at 0 and 15, 30, 90 days from the beginning of the study. Patients were examined in a blind fashion. For the statistical analysis the Student's t test, Mann-Whitney U test, and chi(2) test were performed. RESULTS: Symptoms were statistically significantly improved at day 15 in both groups but group 1 patients had a global score statistically significantly better group 2 (p=0.02). At day 15 group 1 patients had an improvement from baseline values of BUT (p=0.003), fluorescein, and rose bengal score (p=0.000001 and p=0.0004 respectively). Group 2 patients had, at day 15, an improvement of BUT and fluorescein score compared to baseline values (p=0.05 and p=0.0001 respectively). A comparison between the two groups showed better results for group 1 patients at day 15 for rose bengal stain (p=0.01) and for BUT (p=0.05) and fluorescein score (p=0.0003) at day 90. The conjunctival impression cytology showed that group 1 had a statistically significant better total score than group 2 starting from day 15 and lasting throughout the study (p<0.02). Also group 2 patients showed an improvement from baseline values starting from day 30 (p=0.000005). CONCLUSION: Hyaluronate eye drops are useful for treating severe dry eye in Sj?gren's syndrome patients. The use of a formulation with pronounced hypotonicity showed better effects on corneoconjunctival epithelium than the isotonic solution.