What are the commonly used biologicals in ophthalmology for conditions such as age-related macular degeneration, diabetic macular edema, and retinal vein occlusion, and how are they administered and monitored?

Biologicals in Ophthalmology

Anti-VEGF Agents: The Cornerstone of Retinal Disease Management

Anti-VEGF therapy represents the most important class of biologicals in ophthalmology, serving as first-line treatment for neovascular AMD, diabetic macular edema, and retinal vein occlusion-related macular edema. 1

FDA-Approved Anti-VEGF Agents

Ranibizumab (Lucentis/Cimerli)

• Recombinant humanized antibody fragment targeting VEGF-A 2, 3
• FDA-approved for neovascular AMD, diabetic macular edema, diabetic retinopathy, retinal vein occlusion, and myopic CNV 3
• Dosing for neovascular AMD: 0.5 mg (0.05 mL of 10 mg/mL solution) intravitreally once monthly, though less frequent dosing after 3-4 loading doses is acceptable but less effective 3
• Dosing for DME/DR: 0.3 mg (0.05 mL of 6 mg/mL solution) intravitreally once monthly 3

Aflibercept (Eylea)

• Fusion protein that binds VEGF-A, VEGF-B, and placental growth factor 1
• Superior efficacy in DME with moderate visual impairment compared to bevacizumab, particularly in patients with baseline visual acuity <69 ETDRS letters 2, 4
• After three loading doses at 4-week intervals, maintenance dosing every 8 weeks demonstrates comparable efficacy to monthly ranibizumab or aflibercept in neovascular AMD 1, 5

Bevacizumab (Avastin)

• Full-length humanized monoclonal antibody against VEGF-A 2
• Off-label use but widely accepted as a reasonable alternative to ranibizumab and aflibercept for cn-AMD, DMO, RVO-MO, and m-CNV 2, 4
• Most commonly used anti-VEGF agent in clinical practice, accounting for 64.6% of all anti-VEGF injections despite lacking FDA approval for ophthalmic indications 6

Faricimab (Vabysmo)

• Bispecific monoclonal antibody that neutralizes both VEGF-A and angiopoietin-2, offering dual pathway inhibition 2
• Administered every 4-8 weeks during the first 12 months, with fewer injections in subsequent years 2
• Notable safety signal: Elevated disproportionality for anterior segment inflammation including anterior chamber flare (ROR = 270.95), iridocyclitis (ROR = 214.60), and pseudoendophthalmitis (ROR = 262.31) 7

Brolucizumab (Beovu)

• Single-chain antibody fragment targeting VEGF-A 7
• Strongest association with intraocular inflammation (ROR = 633.32) and vitritis (ROR = 1769.33) among all anti-VEGF agents 7
• Should be reserved for cases where other anti-VEGF agents have failed due to elevated inflammation risk 7

Administration Protocol for Anti-VEGF Therapy

Initial Treatment Phase

• Three loading doses at exactly 4-week intervals for neovascular AMD, DME, and RVO-related macular edema 1, 5
• Each visit must include biomicroscopic fundus examination and OCT imaging to assess for subretinal or intraretinal fluid 1

Maintenance Treatment Regimens

• Monthly injections: Most intensive but minority of retina specialists use this approach 1
• Treat-and-extend: Anti-VEGF injection following an interval based on treatment response, extending by 2-week increments if no disease activity 1, 5
• PRN (as-needed): Based on presence or absence of subretinal or intraretinal fluid on OCT 1
• Fixed bimonthly (aflibercept): Every 8 weeks after loading phase, with comparable efficacy to monthly dosing in first year 1, 5

Critical Monitoring Requirements

• OCT at each visit to evaluate treatment response and detect persistent or recurrent fluid 1, 2
• Fluorescein angiography and OCTA when clinically indicated to detect signs of active exudation or disease progression 1
• Immediate examination required if patients report symptoms of endophthalmitis, retinal detachment, or decreased vision 1

Safety Profile and Adverse Events

Common Ocular Adverse Events

• Conjunctival hemorrhage, eye pain, vitreous floaters, and increased intraocular pressure (most frequent) 3
• Endophthalmitis risk varies by agent: aflibercept (ROR = 208.88), ranibizumab (ROR = 114.69), faricimab (ROR = 99.75), brolucizumab (ROR = 56.15) 7

Serious Complications

• Endophthalmitis and retinal detachment may occur following intravitreal injections, requiring immediate recognition and treatment 3
• Intraocular pressure elevation noted both pre- and post-injection, necessitating IOP monitoring 3
• Arterial thromboembolic events: Potential risk following intravitreal VEGF inhibitor use 3
• Increased mortality: Fatal events occurred more frequently in DME/DR patients treated monthly with ranibizumab compared to control 3

Agent-Specific Safety Concerns

• Brolucizumab: Highest signal for IOI and retinal vasculitis, limiting its use to refractory cases 7
• Faricimab: Elevated anterior segment inflammation signals warrant careful monitoring for iritis and iridocyclitis 7
• As-needed regimens: Associated with 1.8% mortality increase (RR: 2.0) compared to monthly treatment in cn-AMD patients 4

Intravitreal Corticosteroids

Dexamethasone Intravitreal Implant (Ozurdex)

• Second-line therapy for macular edema associated with RVO and DME due to significant ocular side effects 1
• Primary concerns include secondary glaucoma and cataract formation 1
• Reserved for patients who are poor responders to anti-VEGF therapy or have contraindications to anti-VEGF agents 1

Triamcinolone Acetonide

• Intravitreal corticosteroid with demonstrated benefit in CRVO and BRVO with macular edema 1
• Considered second-line due to elevated IOP risk and cataract progression 1

Triamcinolone Suprachoroidal Injection (Xipere)

• FDA-approved exclusively for macular edema associated with uveitis, not for retinal vasculitis 8
• Formulated for suprachoroidal injection as single 4 mg (0.1 mL) dose, not for repeated intravitreal administration 8
• Critical pitfall: Do not confuse uveitis-associated macular edema with retinal vasculitis—these require different treatment approaches 8

Adjunctive Laser Therapy

Panretinal Photocoagulation (PRP)

• Best treatment for iris neovascularization or retinal neovascularization following CRVO 1
• Dense peripheral PRP decreases risk of progression to neovascular glaucoma, though it does not improve visual acuity 1
• Anti-VEGF agents used adjunctively when complete PRP insufficient to control angiogenesis 1

Focal Laser Treatment

• Demonstrated therapeutic benefit in BRVO with macular edema, though anti-VEGF therapy now preferred as first-line 1

Clinical Outcomes and Prognostic Factors

Real-World Visual Outcomes

• Neovascular AMD: Mean VA change of +3.1 letters at 1 year, -0.2 letters at 3 years, -2.2 letters at 5 years after mean of 7.6,19.5, and 32 injections respectively 9
• DME: Mean VA change of +4.7 letters at 1 year, +3.3 letters at 3 years, +3.1 letters at 5 years after mean of 6.2,15.4, and 26.0 injections respectively 9
• BRVO-ME: Mean VA change of +9.5 letters at 1 year, +7.7 letters at 3 years after mean of 7.1 and 18.2 injections respectively 9
• CRVO-ME: Mean VA change of +8.3 letters at 1 year, +6.0 letters at 3 years after mean of 7.3 and 18.8 injections respectively 9

Treatment Intensity Correlation

• Mean VA change correlates directly with treatment intensity across all four disorders at 1,3, and 5 years 9
• Eyes with baseline VA ≥20/40 tend to lose vision, while eyes with progressively worse baseline VA experience progressively greater VA gain 9

Common Pitfalls and How to Avoid Them

Delayed Treatment Initiation

• Early treatment within 2 years of diagnosis significantly reduces legal blindness and visual impairment in wet AMD 5
• Ancillary personnel must recognize that patients with new symptoms (visual loss, metamorphopsia, scotoma) require prompt examination 1

Inadequate Loading Phase

• Three loading doses at exactly 4-week intervals are mandatory—do not extend intervals during loading phase 1, 5

Premature Treatment Discontinuation

• Limited visual outcomes in practice often reflect insufficient treatment intensity rather than drug failure 9
• Mean change in VA correlates with treatment intensity; undertreatment leads to vision loss 9

Ignoring Fellow Eye Risk

• Fellow eye without CNV remains at high risk (up to 36% over 10 years without AREDS2 supplementation) 1, 5
• Patients with exceptionally high risk (advanced AMD in one eye, large drusen with RPE changes in fellow eye) require examination every 6-12 months even without symptoms 1

Misunderstanding Quality of Life Impact

• Macular edema causes substantial decrease in vision-related quality of life 1
• Patients with neovascular AMD report substantial decline in quality of life and increased need for assistance with daily activities as visual acuity worsens 5