Treating ophthalmological conditions

There have been a number of recent developments in the treatments available for use in retinal disease. 

The evolution of intravitreal therapy has revolutionised the management of common conditions, particularly diabetic macular oedema (DMO), age-related macular degeneration (ARMD) and retinal vein occlusion (RVO). 

Diabetic macular oedema

DMO is the most common cause of visual loss in diabetic patients, particularly in those with type 2 diabetes mellitus. 

Diabetic retinopathy is the second most common reason for registration as blind among working adults (aged 16-64) in Ireland, with an incidence rate of 11.3%.¹

Risk factors include duration of diabetes, poor metabolic control (namely glycaemic, blood pressure, lipid and body mass index) and smoking. Hyperglycaemia results in microangiopathy affecting vasculature from an arteriolar down to a capillary level. Pericyte loss and endothelial damage cause a combination of microvascular occlusion and leakage. Microaneurysm formation ensues alongside exudation of plasma into the retinal layers. Clinically, this is seen as foveal oedema and hard exudation, or foveal ischaemia.

Age-related macular oedema

ARMD is the most common cause of blindness over 50 years of age in the Western world. The prevalence rate in Europe has been estimated at 1.5% over the age of 40.² It can be classified as dry or wet. Risk factors include increasing age, smoking and family history. 

In dry ARMD, there is a slowly progressive loss of retinal pigment epithelial cells from beneath the retina, with or without loss of overlying photoreceptors. Bruch’s membrane can eventually thicken, resulting in the clinical appearance of drusen, and the choriocapillaris becomes atrophic. The patient develops a central scotoma. 

Wet ARMD has a more rapid progression, and is characterised by choroidal neovascular membrane formation (CNVM). This comprises an ingrowth of fragile blood vessels from the choroid, through the retinal pigment epithelium into the subretinal space, thought to be driven by vascular endothelial growth factor (VEGF). 

Advanced dry ARMD can be associated with as profound a loss as seen in wet ARMD. 

Retinal vein occlusions

RVOs are classified as central (CRVO) or branch (BRVO). The 15-year cumulative incidence rate is 0.5% for CRVO and 1.8% for BRVO.³

The risk factors, clinical course and therapies vary according to the subtype of RVO. CRVO is typically found in individuals over 50. Hypertension, dyslipidaemia, atherosclerotic cardiovascular disease, diabetes mellitus and primary open angle glaucoma are risk factors. 

The pathophysiology is thought to relate to the formation of a thrombus due to turbulent flow, eg. atherosclerosis in the neighbouring central retinal artery affecting endothelial integrity in the vein by altering haemodynamics. 

CRVO is classified as ischaemic (25%) or non-ischaemic (75%), as determined by fluorescein angiography. Ischaemic CRVO has a poorer outcome, and results in neovascularisation within the eye in one-third of cases. Non-ischaemic CRVO has a better prognosis, though one-third will progress to ischaemia in three years. 

BRVO occurs most frequently at the site of artery-venous crossing, with a similar pathophysiology to CRVO. Hypertension is the most common risk factor. Around 50-60% of cases retain visual acuity (VA) of > 6/12 at one year. 

Treatments

Laser

While scatter laser panretinal photocoagulation is the treatment for proliferative diabetic retinopathy, a less intense method of laser is also an option in DMO. This can take the form of focal laser to an area of microaneurysms and oedema, or grid laser for diffuse macular oedema. Risks include development of paracentral scotoma. Patients are monitored every three to four months for a visual and anatomical response. Three years on from the initiation of treatment of DMO with focal laser, patients gain an average of five letters of VA.⁴

Photodynamic therapy is a treatment option in neovascular ARMD. It involves the injection of intravenous verteporfin (a photosensitising dye with affinity for choroidal neovascular tissue). 

A transpupillary diode laser is used to irradiate the neovascular complex. This results in the induction of free radicals which cause thrombosis in the vessels, thereby occluding them. 

This treatment slows vision loss rather than improving it, and has been replaced by the use of anti-VEGF therapy in a number of instances. 

Anti-VEGF therapy

There are a number of anti-VEGF therapies in use. These include bevacizumab (licensed for metastatic colon cancer, off-licence for intraocular use), ranibizumab (licensed for intraocular use in ARMD/DMO/RVO) and, more recently, aflibercept (licensed for intraocular use in ARMD). 

The rate of blind registration in Denmark and Israel for these conditions has dramatically changed since 2005, which is attributed to the introduction of anti-VEGF agents. 

Bevacizumab is a recombinant humanised monoclonal antibody to VEGF. 

Ranibizumab is a humanised recombinant monoclonal antibody fragment to VEGF, with a molecular size three times smaller than bevacizumab. 

Aflibercept, also known as VEGF Trap-Eye, is a fully human fusion protein consisting of portions of VEGF receptors 1 and 2, which binds all forms of VEGF-A, along with the related placental growth factor. 

Risk factors of intravitreal anti-VEGF include endophthalmitis (< 0.1%), retinal detachment, damage to the intraocular lens and uveitis. 

Ranibizumab has been shown in randomised controlled multi-centre trials to maintain vision in 94% of patients at two years, and to improve vision in 40%.^{5, 6}

When compared to bevacizumab in multi-centre non-inferiority trials of monthly dosing regimens, both show similar levels of gain in visual acuity – 8 (bevacizumab) versus 8.5 (ranibizumab) letters gained in acuity at one year.⁷

A comparison study between the two drugs carried out in the USA-CATT found a slightly higher rate in the bevacizumab group of adverse systemic events.⁷ This, however, could not be attributed to any one organ system and was not statistically significant. This was not found in a similar study in the UK-IVAN.⁸

Ranibizumab has been shown to be beneficial in DMO (significantly more patients showed gains in visual acuity and anatomical improvement), as well as in RVO with macular oedema.^9,10 

Aflibercept has recently been shown to be non-inferior to ranibizumab in the treatment of wet ARMD. The main difference between the two drugs was a need for fewer injections in a one-year time frame.¹¹

Aflibercept has also shown potential in treating DMO, with patients showing better visual gain at one year when compared to laser,¹² and in RVO with macular oedema.¹³ Longer-term studies are awaited. 

Peri/intraocular steroids

The use of intravitreal steroid injection, eg. triamcinolone, has been superseded in some ways by anti-VEGF therapies. It remains a useful treatment option, however. This includes, but is not limited to, DMO which is refractory to anti-VEGF and laser, and RVO with macular oedema. 

Risks include raised intraocular pressure, and accelerated cataract formation, as well as the inherent risks of an intraocular procedure including retinal detachment, and endophthalmitis. 

Implantable devices are now coming into more widespread use, with a dexamethasone implant available. It has been shown to be beneficial in RVO with macular oedema.¹⁴

Vitamin supplementation

In 2001, AREDS (Age Related Eye Disease Study) showed a benefit of taking daily high doses of vitamins C and E, beta-carotene, zinc and copper to reduce the risk of advanced ARMD for those with specific early features of the disease.¹⁵ There was a 25% reduction in progression rates. 

Beta-carotene was associated with a higher rate of lung cancer, particularly in smokers. In 2013, AREDS II did not find any additional benefit in taking omega 3, lutein or zeaxanthin in combination with the original supplement. 

Future treatments

Emerging treatments in clinical trials include a plethora of monoclonal antibodies, and implantable drug-eluting formulations. 

Fluocinolone implants have been approved in a number of European countries for longstanding DMO. They are associated with cataract development (82%), and a risk of raised intraocular pressure (37%), but show benefit over sham in improving visual acuity.¹⁶ 

Sonepcizumab is an antibody to S1P – a growth factor which modulates neovascularisation and fibrosis. It is in phase I trials. 

HI-con1 is an antibody to tissue factor in phase I trials, a growth factor expressed at high levels in the new vessels of wet ARMD. 

E10030, or Fovista, is an antibody to platelet-derived growth factor B, and has been shown to be superior when used in combination with ranibizumab to ranibizumab alone for wet ARMD in phase II clinical trials. 

Lampalizumab is a monoclonal antibody to complement factor D, a rate-limiting enzyme in the complement factor pathway. 

Increased activation of the pathway is associated with macular degeneration. It is in phase II trials for dry ARMD. Early evidence suggests that it can halt progression of geographic atrophy. This could be the first treatment for dry AMD. 

Radiation therapy in combination with ranibizumab is also being examined for a specific subtype of wet ARMD known as polypoidal choroidal vasculopathy. This involves the delivery of radiation directly to the macula through a pre-calculated trans-scleral route using the Oraya-IRay device. 

Summary

Many new treatment options are on the horizon for treating retinal diseases, with outcomes from clinical trials awaited. Those which have filtered into common clinical use include intravitreal anti-VEGF injections. Older therapies such as laser and periocular/intraocular steroids continue to have a role. 

References

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2. Augood CA, Vingerling JR, de Jong PT et al. Prevalence of age-related maculopathy in older Europeans: the European Eye Study (EUREYE). Arch Ophthalmol 2006; 124(4): 529-535
3. Klein R, Moss SE, Meuer SM, Klein BE. The 15-year cumulative incidence of retinal vein occlusion: the Beaver Dam Eye Study. Arch Ophthalmol 2008; 126(4): 513-518
4. Beck RW, Edwards AR, Aiello LP et al. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol 2009; 127(3): 245-251
5. Brown DM, Michels M, Kaiser PK et al. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthalmology 2009; 116(1): 57-65 e5
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10. Brown DM, Campochiaro PA, Singh RP, Li et al. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology 2010; 117(6): 1124-1133 e1
11. Heier JS, Brown DM, Chong V et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 2012; 119(12): 2537-2548
12. Do DV, Nguyen QD, Boyer D et al. One-year outcomes of the da Vinci Study of VEGF Trap-Eye in eyes with diabetic macular edema. Ophthalmology 2012; 119(8): 1658-1665
13. Boyer D, Heier J, Brown DM et al. Vascular endothelial growth factor Trap-Eye for macular edema secondary to central retinal vein occlusion: six-month results of the phase 3 COPERNICUS study. Ophthalmology 2012; 119(5): 1024-1032
14. Haller JA, Bandello F, Belfort R Jr et al. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology 2011; 118(12): 2453-2460
15. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 2001; 119(10): 1417-1436
16. Sanford M. Fluocinolone acetonide intravitreal implant (Iluvien(R)): in diabetic macular oedema. Drugs 2013; 73(2): 187-193