Age-related macular degeneration: clinical guidelines

List of Abbreviations

AMD ― age-related macular degeneration

HIV ― human immunodeficiency virus

GA ― geographic atrophy

ELISA — enzyme-linked immunosorbent assay

ICD-10 — International Classification of Diseases 10th Revision

NE — neuroepithelium

OCT ― optical coherence tomography

OCT-A ― optical coherence tomography angiography

PCV ― polypoidal choroidal vasculopathy

PCR — polymerase chain reaction

RPE ― retinal pigment epithelium

RAP ― retinal angiomatous proliferation

RNA — ribonucleic acid

FA ― fluorescein angiography

CNV ― choroidal neovascularization

AREDS ― Age-Related Eye Disease Study

VEGF — vascular endothelial growth factor

** – vital and essential drugs

Terms and Definitions

Ocular biomicroscopy is an in vivo visual examination method of the optical media and ocular tissues based on creating contrast between illuminated and non-illuminated areas, performed using a slit lamp and additional diagnostic lenses (specifically, for fundus biomicroscopy).

Hemorrhagic pigment epithelium (RPE) or neuroepithelium (NE) detachment is a clinical manifestation of the wet form of AMD that develops due to a breach in the vessel integrity of choroidal neovascularization (CNV) and presents as an accumulation of blood beneath the RPE or NE.

Geographic atrophy (GA) is an area of RPE absence and choriocapillaris regression, with secondary photoreceptor atrophy, developing as a result of dry AMD progression.

Drusen are accumulations of impaired metabolism products located extracellularly between the inner layer of Bruch's membrane and the RPE basement membrane.

Intraretinal fluid (neuroepithelium (NE) edema) is an intercellular accumulation of fluid in the NE layers, manifesting as retinal thickening.

Fundus autofluorescence imaging is a diagnostic method based on the ability of fluorophores (specifically lipofuscin and its compounds) to autofluoresce upon excitation without the administration of dyes.

Lipid (hard) exudates are accumulations of lipoproteins in the NE layers resulting from increased vascular permeability.

Neovascular RPE detachment is a separation between the RPE and Bruch's membrane due to the presence of CNV fibrovascular tissue (fibrovascular RPE detachment) or fluid accumulation resulting from the transudative activity of CNV (serous neovascular RPE detachment).

Optical coherence tomography (OCT) is a diagnostic non-invasive, non-contact in vivo visualization method for qualitative and quantitative analysis of the morphological features of fundus structures, based on the principle of optical interferometry.

Optical coherence tomography angiography (OCT-A) is a diagnostic non-invasive, non-contact in vivo visualization method for qualitative and quantitative analysis of microcirculation in fundus structures, taking into account fundus layer segmentation.

Subretinal fluid (serous NE detachment) is an accumulation of fluid beneath the NE.

Fluorescein angiography (FA, sodium fluorescein angiography) is a diagnostic method that allows the detection of vascular bed abnormalities in the fundus and the evaluation of the state of the outer and inner blood-retinal barriers by recording the passage of a dye (intravenously administered sodium fluorescein) through the ocular vessels using photo- and video-monitoring.

Photodynamic therapy is a method of treating certain eye diseases based on the use of photosensitive substances (photosensitizers) and light of a specific wavelength for the purpose of occluding pathological vessels.

Choroidal neovascularization (CNV) are newly formed vessels growing as a result of pathological neoangiogenesis from the choriocapillary network through defects in Bruch's membrane beneath the RPE and/or NE.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Age-related macular degeneration (AMD) is a chronic, progressive, multifactorial disease characterized by a degenerative process in the retinal pigment epithelium (RPE), Bruch's membrane, and choriocapillaris of the central fundus zone with secondary damage to the neuroepithelium (NE) and is the main cause of central vision loss among the elderly population.

Typical signs of AMD include:

• drusen;

• changes in the retinal RPE;

• geographic atrophy (GA);

• choroidal neovascularization (CNV).

Special forms of wet AMD are considered to be:

• retinal angiomatous proliferation (RAP);

• polypoidal choroidal vasculopathy (PCV).

RAP is a special form of wet AMD characterized by the onset of a proliferative process in the retinal vascular network followed by the formation of CNV and a retino-choroidal anastomosis.

PCV is a special form of wet AMD characterized by the development of aneurysmal dilations at the terminals of an abnormally branching choroidal vascular network.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The etiology is undetermined. As a rule, the disease occurs at the age of 50 years and older [1]. The role of genetic predisposition, the influence of smoking, and other risk factors are discussed [2].

AMD represents a chronic degenerative process in the RPE, Bruch's membrane, and choriocapillaris. Lipid peroxidation reactions, inflammation, complement system impairment, deficiency of defense mechanisms, and other factors play a role in pathogenesis [3].

The retina is characterized by a high oxygen demand, making it very sensitive to oxidative damage during which free radicals are produced in excess. A protective role is played by the "yellow" macular pigment (oxycarotenoids lutein and zeaxanthin), which absorbs the short-wave portion of blue light and participates in antioxidant defense. The amount of oxycarotenoids decreases with age. Activation of lipid peroxidation leads to the formation of large molecular chains that are not recognized by RPE cell enzymes, do not break down, and accumulate, forming drusen [4].

In addition, with age, the thickness of Bruch's membrane increases, its permeability decreases, and the density of the choriocapillary network diminishes. As a result, the oxygen supply to RPE cells worsens. When defense mechanisms are insufficient, such changes lead to an increased production of growth factors and matrix metalloproteinases. Growth factors promote the growth of newly formed vessels, while metalloproteinases cause the appearance of defects in Bruch's membrane [5].

Clinically, AMD typically begins with changes in the RPE and the appearance of hard drusen, followed by the formation of soft drusen. Progressive RPE loss combined with degenerative changes in the choriocapillaris lead to degenerative changes in the NE and the development of GA. The growth of newly formed vessels in the choriocapillary layer is associated with the development of the wet form of AMD, also called exudative or neovascular. Upon the appearance of defects in Bruch's membrane, CNV spreads beneath the RPE and NE. The activity of newly formed vessels may manifest as hemorrhages, intraretinal fluid, subretinal fluid, or fluid beneath the RPE. The final stage of the process development—the formation of a subretinal fibrous scar in the central region of the fundus—is associated with significant central vision loss [6].

1.3 Epidemiology of the Disease or Condition

In economically developed countries, AMD is the leading cause of visual disability among the elderly population. According to a meta-analysis of 39 population-based studies covering 129,664 people from five ethnic groups, the estimated number of AMD patients worldwide in 2020 was 196 million, with a projected growth to 288 million patients by 2040 [7].

It has been proven that the development of AMD is associated with age. According to the Beaver Dam Eye Study, the detection rate of AMD increased from 4.2% for people aged 43–54 years to 46.2% among people older than 75 years [8]. In the near future, the growth of the population aged over 60 will inevitably cause an increase in the prevalence of AMD in developed countries. All this makes it necessary to consider AMD as a significant medical and social problem [8, 9].

In the Russian Federation, large-scale epidemiological studies of AMD have not been conducted. According to federal statistical observation data (form No. 12) "Information on the number of diseases registered in patients living in the service area of a medical organization", in 2018, a total of 319,340 patients with macular and posterior pole degeneration (H35.3) were registered in the Russian Federation.

Risk factors:

1. The main risk factor for developing AMD is age [10];

2. Smoking doubles the risk of developing AMD. Quitting smoking leads to a reduced risk of AMD (the risk of developing AMD in those who have not smoked for more than 20 years is comparable to that of non-smokers) [11];

3. Ethnic factor. AMD affects Europeans more frequently than representatives of other ethnic groups [12];

4. Family history. Genetic factors [13, 14];

5. Arterial hypertension and lipid metabolism disorders [15];

6. Low blood serum antioxidant concentration [16].

1.4 Features of Coding the Disease or Condition

H35.3 — Degeneration of macula and posterior pole

1.5 Classification of the disease or condition

The classification adopted in routine clinical practice [17] distinguishes:

• dry (non-exudative; in late stage - atrophic) form of AMD,

• wet (neovascular or exudative) form of AMD.

The Age-Related Eye Disease Study (AREDS) classification [18], adopted in clinical trials and widely used in clinical practice, distinguishes the following stages:

1. No AMD (AREDS Category 1): no changes or a few small drusen (diameter <63 microns);

2. Early AMD (AREDS Category 2, early dry AMD): multiple small drusen, a few intermediate drusen (diameter 63 to 124 microns), or mild retinal pigment epithelium (RPE) abnormalities;

3. Intermediate AMD (AREDS Category 3, intermediate dry AMD): extensive intermediate drusen, at least one large drusen (diameter ≥125 microns), or geographic atrophy (GA) not involving the foveal center;

4. Late (advanced) AMD (AREDS Category 4): characterized by one or more of the following features (in the absence of other causes):

• Geographic atrophy (GA) involving the foveal center – atrophic (dry) form;

• Choroidal neovascularization (CNV) with various manifestations (neurosensory retinal and/or RPE detachment, neurosensory retinal edema, hemorrhages, hard (lipid) exudates, etc.) – wet (neovascular, exudative) AMD;

• Fibrovascular disciform scar formation (end-stage wet AMD).

1.6 Clinical presentation of the disease or condition

Drusen are the hallmark fundus manifestation of AMD. Drusen are classified into hard, soft, and reticular pseudodrusen.

Hard cuticular drusen are a manifestation of early-stage AMD and are associated with the deposition of drusenoid material beneath the RPE. On fundus biomicroscopy, they appear as small, well-demarcated yellowish foci in the macula. On OCT scans, they present as localized elevations of the RPE band with medium reflectivity; the base diameter of the elevation typically does not exceed 50 µm. On FFA, drusen locations correspond to pinpoint early hyperfluorescence without dye leakage. Hard cuticular drusen are considered a relatively benign manifestation of the disease, with the 5-year risk of progression to advanced AMD not exceeding 1.3% [18].

Soft drusen form as a result of large-volume deposition of drusenoid material beneath the RPE. The presence of at least one large drusen (>125 µm) defines progression of the disease to the intermediate stage. On fundus biomicroscopy, drusen are visible as large yellowish lesions in the macula with indistinct margins. On OCT scans, they are identified as localized RPE detachments (avascular, drusenoid pigment epithelial detachments) with medium-reflective content. On FFA, they are characterized by late, faint hyperfluorescence without dye pooling/leakage, or they may be hypofluorescent. The risk of disease progression to late-stage AMD in the presence of unilateral intermediate AMD is 18%, and for bilateral disease, 27% [18].

Reticular drusen (reticular pseudodrusen) represent a distinct phenotype and are associated with the deposition of drusenoid material above the RPE. This type of drusen is virtually undetectable on fundus biomicroscopy. On OCT scans, they present as medium-reflective material above the RPE appearing as conical projections towards the neurosensory retina. Reticular drusen are barely visible on FFA. Fundus autofluorescence (where they appear as hypoautofluorescent foci) and infrared reflectance imaging are the most informative diagnostic modalities. Reticular drusen are associated with an increased risk of progression to late-stage AMD [8].

Confluent drusen are a sign of disease progression. They form a larger avascular RPE detachment. Avascular RPE detachment can be serous or drusenoid, depending on the reflectivity of the material beneath the detached RPE.

Over time, drusen may undergo the following dynamic changes:

• Hard drusen may enlarge and transform into soft drusen;

• Soft drusen may also enlarge, forming confluent drusen (avascular RPE detachments);

• Calcifications may develop within drusen, appearing as glistening crystals on ophthalmoscopy;

• Spontaneous regression of drusen may occur, which can be associated with progression of the disease to advanced AMD [19].

Macular pigmentary changes are also a manifestation of AMD. The appearance of hyperpigmented areas is associated with RPE cell migration and is considered one of the predisposing factors for CNV development.

GA develops as a result of dry AMD progression. In GA, the RPE is primarily affected; in addition, degeneration of the choriocapillaris and outer retinal layers occurs. On fundus biomicroscopy, areas of GA appear as well-circumscribed patches of depigmentation with clearly visible large choroidal vessels. OCT scans show thinning of the neurosensory retina, thinning and disruption of the RPE band, increased penetration of the scanning beam into the underlying tissues (hypertransmission), and potential outer retinal tubulation (loss of photoreceptor architecture in response to disruption of RPE adhesion). On FFA, atrophic zones appear as areas of "window defect" hyperfluorescence with sharp borders. GA is associated with significant, irreversible loss of central vision [6].

Wet AMD is characterized by the development of CNV – the proliferation of new vessels through defects in Bruch's membrane beneath the RPE or beneath the neurosensory retina. Detecting signs of CNV activity is crucial when deciding to initiate/resume treatment of a patient with wet AMD with intravitreal anti-VEGF injections, as well as when considering photodynamic therapy (in specific forms of wet AMD) or laser photocoagulation (for extrafoveal CNV when anti-VEGF therapy is not feasible). Signs of activity may include decreased visual acuity secondary to this condition and/or deteriorating anatomical parameters: the appearance of macular hemorrhages (including hemorrhagic RPE or neurosensory retinal detachments) and/or the appearance/increase of intraretinal fluid (neurosensory retinal edema) and/or the appearance/increase of subretinal fluid (neurosensory retinal detachment) and/or the appearance/increase of sub-RPE fluid and/or dye leakage on FFA.

OCT is the most informative modality for detecting retinal changes characteristic of active CNV (pathological fluid collections).

The presence and expansion of CNV may persist for a long time without exudative activity.

Based on anatomical location, CNV is classified into the following types:

• Type 1 CNV: localized beneath the RPE (corresponds to occult CNV in the FFA-based classification);

• Type 2 CNV: localized above the RPE (corresponds to classic CNV in the FFA-based classification);

Type 1 CNV (occult CNV) is suspected when fundus biomicroscopy reveals pigmentary changes; the degree of retinal thickening can vary, depending on the presence of intra- and/or subretinal fluid and the height of the fibrovascular pigment epithelial detachment (PED). OCT scans show a neovascular PED and possible signs of CNV activity. Depending on the extent of CNV beneath the detached RPE, it is classified as a fibrovascular PED (the PED is filled with CNV tissue) or a serous neovascular PED (the detachment forms as a result of transudation from neovascular vessels). FFA reveals stippled hyperfluorescence without an identifiable source of leakage, and the CNV vascular network is not clearly delineated. In active CNV, the intensity of hyperfluorescence increases due to fluorescein leakage. The neovascular network is well visualized on OCTA, except in cases where the CNV is located beneath a high serous neovascular PED.

Type 2 CNV (classic CNV) manifests on fundus biomicroscopy as a prominent, elevated grayish lesion beneath the neurosensory retina. OCT scans demonstrate a spindle-shaped hyperreflective lesion above the RPE line, with possible signs of CNV activity. On FFA, the neovascular network is well defined, with bright, homogeneous hyperfluorescence observed as the transit progresses. In cases of active CNV, pronounced fluorescein leakage from the neovascular vessels intensifies throughout the study. OCTA clearly delineates the neovascular network above the RPE.

Mixed CNV is categorized into predominantly classic (where the classic component accounts for at least 50% of the total lesion area) and minimally classic (classic component is present, but comprises less than 50% of the total lesion area).

Type 3 CNV includes retinal angiomatous proliferation (RAP), which is characterized by the initiation of neovascularization within the retinal vascular plexus, followed by the formation of CNV and a retinochoroidal anastomosis. Early RAP is invisible on fundus biomicroscopy. A combination of reticular drusen, drusenoid PED, and a hyperreflective focus at its apex (on OCT) warrants high clinical suspicion. Progression of retinal vessel proliferation is accompanied by hemorrhages, neurosensory retinal edema, and hard exudates. As it progresses, RAP acquires clinical features similar to Type 1 CNV. Informative diagnostic modalities include OCTA and FFA.

PCV is clinically similar to type 1 CNV, but differs in a more severe course, a tendency to subretinal hemorrhages, diffuse RPE damage, and choroidal thickening. OCT and OCT-A are informative imaging methods for abnormal choroidal vessels, which reveal typical signs of PCV: RPE protrusions with visualization of polyps, the "double-layer" sign (separate visualization of Bruch's membrane and the RPE), and choroidal thickening.

A scar-atrophic focus is formed at the final stage of CNV development. Ophthalmoscopy reveals a round, grey-white lesion, often with pigment deposition. This clinical picture is associated with irreversible central vision loss and an unfavorable prognosis for treatment.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for diagnosing AMD *

Note: * - using AREDS recommendations [18].

2.1 Complaints and Anamnesis

Comments: in early AMD, there are no complaints. In intermediate AMD, there are no complaints or there may be complaints of some decrease in vision, distortion of straight lines (metamorphopsia), and missing letters when reading. In wet AMD, complaints of pronounced decrease in visual acuity, line distortion (metamorphopsia), and reading difficulties are characteristic. In atrophic AMD, patients complain of a significant decrease in visual acuity and the inability to read.

Comments: it is necessary to find out about cases of AMD among close relatives, smoking status, and the presence of concomitant ocular and systemic diseases in order to identify risk factors for AMD progression and assess the risk of complications from intravitreal drug administration.

2.2 Physical Examination

Comments: the choice of specialist profile is determined depending on the patient's concomitant systemic disease and risk factors for systemic complications.

2.3 Laboratory Diagnostics

There are no diagnostic criteria for AMD based on clinical laboratory test data.

Comments: the examination is carried out on the basis of voluntary consent (sanitary and epidemiological rules SP 3.1.5.2826-10 "Prevention of HIV infection"). The choice of laboratory test is determined based on the presence of concomitant systemic disease and risk factors for systemic complications in the patient.

2.4 Instrumental Diagnostics

Comments: the necessity and frequency of fundus biomicrophotography using a fundus camera is determined by the ophthalmologist depending on the course of the disease.

Comments: when assessing CNV activity and determining indications for treatment with intravitreal anti-angiogenic medicinal products, quantitative and qualitative parameters of the tomogram should be evaluated, including a differentiated approach to analyzing the effect of pathological fluid of various localizations on vision.

Comments: the necessity and frequency of FA is determined by the ophthalmologist depending on the course of the disease.

Comments: the necessity and frequency of OCT-A are determined by the ophthalmologist based on the specific clinical course of the disease.

Comments: the necessity and frequency of ultrasound examination are determined by the ophthalmologist based on the specific clinical course of the disease.

Comments: the necessity and frequency of computer perimetry are determined by the ophthalmologist based on the specific clinical course of the disease. Additionally, for screening and self-monitoring by patients to detect visual field defects, scotometry (Amsler-Marintchev test) can be used.

Comments: the necessity and frequency of electroretinography are determined by the ophthalmologist based on the specific clinical course of the disease.

2.5 Other Procedures

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative Treatment

Comments: it is necessary to eliminate risk factors for disease progression: smoking cessation, enriching the daily diet with foods rich in natural antioxidants (specifically lutein and zeaxanthin) and polyunsaturated fatty acids (a special therapeutic diet is not required), maintaining physical activity, wearing sunglasses, and managing comorbid somatic pathologies (hypertension, hypercholesterolemia and atherosclerosis, diabetes mellitus, etc.) in collaboration with physicians of other specialties [11, 14, 15, 16, 31, 32, 33]. If risk factors for disease progression are present, the prescription of multivitamins combined with other agents optimized for retinal diseases may be indicated [32, 33].

Comments: according to the AREDS study, the use of an antioxidant vitamin and mineral supplement in patients at high risk of progression to the late stage with a high risk of vision loss (intermediate AMD or late AMD in the fellow eye) was associated with a 25% reduction in the rate of progression and a significant reduction in vision loss by 19% [18].

Comments: currently, there is no effective treatment for the atrophic form of AMD. Proposed treatment methods aim to slow down the progression of visual acuity loss.

3.2 Laser Treatment

Comments: in cases of laser photocoagulation of newly formed vessels, a high risk of CNV recurrence should be taken into account. Prior to laser photocoagulation, precise determination of the size and location of the CNV is required based on comprehensive examination results, including FA, OCT, and potentially OCT-A. Focal laser photocoagulation of the fundus in wet AMD is inferior in efficacy to intravitreal anti-angiogenic therapy and requires regular follow-up of the patient after the intervention.

Comments: photodynamic therapy can be performed as an alternative method or in combination with intravitreal anti-angiogenic drug therapy.

Comments: nanosecond laser retinal stimulation is performed using transpupillary laser application at the macular periphery using a specialized laser system with a wavelength of 532 nm, a pulse duration of 3 nanoseconds, and a spot size of 400 µm. Short nanosecond laser pulses stimulate retinal pigment epithelium cells, triggering their regeneration and restoring disrupted mechanisms of molecular transport between the retina and choroid, while increasing the permeability of Bruch's membrane. Thermal tissue damage is avoided.

3.3 Surgical Treatment

Comments: currently, intravitreal administration of an anti-angiogenic medicinal product is the first-line therapy for wet AMD.

• Ranibizumab** is a humanized antibody fragment directed against vascular endothelial growth factor A (VEGF-A). It selectively binds to VEGF-A (VEGF110, VEGF121, VEGF165), preventing its interaction with receptors on the surface of endothelial cells, which leads to the suppression of neovascularization and endothelial cell proliferation [40].

• Aflibercept** is a recombinant fusion protein consisting of extracellular domain fragments of human VEGF receptors fused to the Fc portion of human immunoglobulin G. It acts as a soluble decoy receptor that binds VEGF-A and placental growth factor with higher affinity than their natural receptors, and thus can inhibit the binding and activation of VEGFR-1 and VEGFR-2 receptors by multiple growth factors involved in pathological angiogenesis [41]. According to clinical trial results, the intervals between aflibercept** injections can be extended up to 16 weeks while maintaining the achieved visual acuity [41].

• Brolucizumab** is a humanized single-chain antibody fragment (scFv, single-chain variable fragment) with a molecular weight of 26 kDa, which is the smallest functional antibody unit. This allows a higher molar dose to be administered compared to previously approved anti-VEGF antibodies, with the potential for a longer duration of action than ranibizumab and higher tissue penetration, as confirmed by preclinical data [39]. Brolucizumab** binds with high affinity to various isoforms of VEGF-A (specifically VEGF110, VEGF121, and VEGF165), thereby preventing VEGF-A from binding to its receptors VEGFR-1 and VEGFR-2.

Faricimab is a humanized bispecific antibody belonging to the immunoglobulin G1 (IgG1) class, which acts by inhibiting two distinct pathways, neutralizing both Ang-2 and vascular endothelial growth factor A. Ang-2 decreases vascular stability by promoting endothelial destabilization, pericyte loss, and pathological angiogenesis, thereby increasing vascular leakage and inflammation. It also sensitizes blood vessels to the activity of VEGF-A, leading to their further destabilization. Ang-2 and VEGF-A act synergistically to increase vascular permeability and stimulate neovascularization. Dual inhibition of Ang-2 and VEGF-A by faricimab reduces vascular permeability and inflammation, suppresses pathological angiogenesis, and restores vascular stability [39; 43; 44].

The prospects of therapy directly depend on its timely initiation and adherence to an optimal injection regimen based on regular dynamic monitoring.

When treating with ranibizumab**, initially 3 or more consecutive monthly intravitreal injections of the medicinal product may be required until maximum stable visual acuity is achieved and/or until signs and symptoms of disease activity disappear (no improvement in visual acuity and/or retinal anatomical parameters within 1 month after the last monthly injection). Once stabilization is achieved, the frequency of follow-up examinations and the interval between intravitreal ranibizumab injections are determined by the physician based on the clinical presentation. An interval of at least 4 weeks should be maintained between injections into the same eye.

When treating with aflibercept**, it is recommended to start with three consecutive monthly intravitreal injections of the medicinal product, followed by the next injection 2 months later. Thereafter, the 2-month intervals between injections can be maintained or extended using a treat-and-extend regimen based on the treating physician's assessment of changes in visual acuity and/or anatomical parameters. When using the treat-and-extend regimen, 2 or 4 weeks are added to subsequent injection intervals to maintain the achieved stable visual acuity and/or anatomical parameters. In case of deterioration in visual acuity and/or anatomical parameters, the injection intervals should be shortened accordingly to a minimum of 2 months. After 12 months of treatment, the frequency of status monitoring and treatment is determined by the physician depending on the course of the disease.

When treating with brolucizumab**, the first 3 doses are administered as intravitreal injections at 4-week intervals (monthly). Thereafter, the physician may individualize injection intervals based on disease activity, assessed by visual acuity and/or anatomical parameters. Disease activity should be assessed 16 weeks (4 months) after the start of therapy. In patients without signs of disease activity, intravitreal administration of the drug is performed every 12 weeks (3 months). In patients with signs of disease activity, administration is performed every 8 weeks (2 months). Subsequently, the physician may adjust injection intervals for each individual patient based on disease activity.

Faricimab treatment is initiated with 4 loading doses administered intravitreally every 4 weeks. Following the loading phase, the subsequent maintenance dosing regimen will be based on anatomical features and visual function characteristics determining the disease course. Assessment of treatment response is recommended at week 20 after the first injection, with a potential re-evaluation at week 24 after the first injection, allowing for individualized therapy depending on the presence or absence of signs of disease activity. In the absence of disease progression, intravitreal injections are recommended every 16 weeks, whereas if signs of progression appear, every 8 or 12 weeks. Follow-up time points to assess the patient's condition are determined at the physician's discretion based on the patient's complaints and general condition; monthly examinations are not required. Subsequently, the physician may adjust injection intervals individually for each patient based on disease activity [39; 43; 44].

In each clinical case, the final decision regarding indications for anti-angiogenic therapy and the choice of the intravitreal injection regimen is made by the physician based on the evaluation of the clinical presentation and disease course.

Prevention of visual acuity decline, even in the absence of its improvement, should be considered a positive outcome compared to the natural history of the disease.

During intravitreal administration of an anti-angiogenic medicinal product, the potential risk of complications such as infectious endophthalmitis, non-infectious intraocular inflammation, iatrogenic cataract, hemophthalmus, retinal detachment, and others must be taken into account.

Contraindications to intravitreal administration of ranibizumab**, or aflibercept**, or brolucizumab**, or faricimab:

- hypersensitivity to the components of the drug;

- active confirmed or suspected ocular infections or periocular infections;

- active intraocular inflammatory process;

- pregnancy and breastfeeding period.

Contraindications to intravitreal administration of prourokinase:

- individual hypersensitivity to the drug components;

- conditions with a high risk of bleeding, including blood disorders;

- active confirmed or suspected ocular infections or periocular infectious processes;

- active intraocular inflammatory process;

- pregnancy and breastfeeding;

- chronic renal failure (serum creatinine level > 0.02 g/L, urea > 0.5 g/L);

- severe hepatocellular failure (blood albumin < 30 g/L).

Comments: the duration of antimicrobial instillation (antiseptics and disinfectants) before and after intravitreal administration of any medicinal product is determined by the physician based on a comprehensive assessment of the risk of infectious complications and the condition of the ocular surface.

3.4 Dietary Therapy

Comments: it is recommended to include foods rich in natural antioxidants, particularly lutein, zeaxanthin, and polyunsaturated fatty acids, in the daily diet.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

5. Prevention and Dispensary Observation

6. Organization of Medical Care

Primary specialized health care is provided by an ophthalmologist in the outpatient department of a medical organization.

Treatment (laser intervention, intravitreal administration of an anti-angiogenic medicinal product, conservative medical treatment, or physiotherapy) is performed by an ophthalmologist in an outpatient setting, a day hospital, or an inpatient setting.

Indication for planned hospitalization in a medical organization:

- the need for intravitreal administration of an anti-angiogenic medicinal product and/or laser treatment and/or medical treatment and/or physiotherapy when outpatient treatment is not feasible.

Indication for emergency hospitalization in a medical organization:

- endophthalmitis as a complication of intravitreal administration of an anti-angiogenic medicinal product [46].

Indication for patient discharge from a medical organization:

1) completion of treatment or one of the stages of specialized, including high-tech, medical care in a 24-hour or day hospital, provided there are no complications of treatment requiring medical correction and/or inpatient medical interventions;

2) refusal of the patient or their legal representative from specialized, including high-tech, medical care in an inpatient or day-care setting;

3) need to transfer the patient to another medical organization.

7. Additional Information

The risk of disease progression to the late stage is increased in smoking patients.

The prospects of treatment with intravitreal anti-angiogenic medicinal products in patients with wet AMD depend on timely initiation of treatment and compliance with the optimal injection regimen in accordance with the drug prescribing information and clinical guidelines based on regular follow-up data.

The most significant manifestations of the disease at the late stage, causing a significant decrease in visual functions, are the development of subretinal fibrosis, massive hemorrhages, and macular atrophy involving the fovea.

Criteria for Evaluating the Quality of Medical Care

Criteria for assessing the quality of primary health care in adults with age-related macular degeneration (ICD-10 codes: H35.3)

Criteria for assessing the quality of specialized medical care in adults with age-related macular degeneration (ICD-10 codes: H35.3)

References

Appendix A1. Working Group Composition

1. Astakhov Yu.S., Group Leader, Doctor of Medical Sciences, Professor at the Department of Ophthalmology with Clinic, Pavlov First Saint Petersburg State Medical University, Vice-President of the Association of Ophthalmologists;

2. Neroev V.V., Academician of the RAS, Professor, Honored Doctor of Russia, Honored Scientist of Russia, Director of the National Medical Research Center of Eye Diseases named after Helmholtz of the Ministry of Health of Russia, President of the Association of Ophthalmologists;

3. Zaitseva O.V., Candidate of Medical Sciences, Deputy Director of the National Medical Research Center of Eye Diseases named after Helmholtz of the Ministry of Health of Russia, Leading Researcher, Executive Director of the Association of Ophthalmologists;

4. Lisochkina A.B., Candidate of Medical Sciences, Associate Professor at the Department of Ophthalmology with Clinic, Pavlov First Saint Petersburg State Medical University, Member of the Association of Ophthalmologists;

5. Nechiporenko P.A., Candidate of Medical Sciences, Assistant Professor at the Department of Ophthalmology with Clinic, Pavlov First Saint Petersburg State Medical University, Member of the Association of Ophthalmologists;

6. Okhotsimskaya T.D., Candidate of Medical Sciences, Physician at the National Medical Research Center of Eye Diseases named after Helmholtz of the Ministry of Health of Russia, Member of the Association of Ophthalmologists;

7. Ryabina M.V., Candidate of Medical Sciences, Senior Researcher at the National Medical Research Center of Eye Diseases named after Helmholtz of the Ministry of Health of Russia, Member of the Association of Ophthalmologists.

8. Shadrichev F.E., Candidate of Medical Sciences, Head of the Ophthalmological Department of the Saint Petersburg Territorial Diabetological Center, Assistant Professor at the Department of Ophthalmology with Clinic, Pavlov First Saint Petersburg State Medical University, Member of the Association of Ophthalmologists;

No conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of these clinical guidelines:

• Ophthalmologists;

• General practitioners (family medicine)

Methods used to collect/select evidence: searching in electronic databases; analysis of current scientific developments on the issue of AMD in Russia and abroad; synthesis of practical experience of Russian and foreign specialists. Description of methods used to collect/select evidence: the evidence base for the recommendations includes publications included in the Cochrane Library, EMBASE, and MEDLINE databases, as well as monographs and articles in leading specialized peer-reviewed domestic medical journals on this topic. Methods used to assess the quality and strength of evidence: expert consensus, significance assessment in accordance with the rating scheme.

Table 1. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing levels of evidence (LE) for prevention, treatment and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)

Table 3. Scale for assessing grades of recommendation (GR) for prevention, diagnosis, treatment and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions)

Procedure for updating clinical guidelines.

The clinical guidelines update mechanism provides for their systematic revision—at least once every three years, as well as upon the emergence of new evidence-based data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Current instructions for the medicinal products mentioned in these clinical guidelines can be found at http://grls.rosminzdrav.ru

Table 4. Dosage, route of administration, and treatment regimens of medicinal products

2. International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10). World Health Organization.

3. Nomenclature of Medical Services. Order of the Ministry of Health of the Russian Federation No. 804n dated October 13, 2017, "On Approval of the Nomenclature of Medical Services."

4. Federal Law No. 323-FZ "On the Fundamentals of Protecting Citizens' Health in the Russian Federation" dated November 21, 2011.

5. Procedure for Providing Medical Care to the Adult Population for Diseases of the Eye, Its Adnexa, and Orbit. Order of the Ministry of Health of Russia No. 902n dated November 12, 2012, "On Approval of the Procedure for Providing Medical Care to the Adult Population for Diseases of the Eye, Its Adnexa, and Orbit."

6. List of Vital and Essential Drugs for Medical Use for 2020. Decree of the Government of the Russian Federation No. 2406-r dated October 12, 2019, "On Approval of the List of Vital and Essential Drugs for Medical Use for 2020, the list of drugs for medical use, the list of drugs intended for persons with hemophilia, cystic fibrosis, pituitary dwarfism, Gaucher disease, malignant neoplasms of lymphoid, hematopoietic and related tissues, multiple sclerosis, hemolytic-uremic syndrome, juvenile onset arthritis, mucopolysaccharidosis types I, II, and VI, persons after organ and/or tissue transplantation, and the minimum assortment of drugs required for the provision of medical care."

7. SanPiN 2.1.3.2630-10 "Sanitary and Epidemiological Requirements for Organizations Engaged in Medical Activity."

8. Order of the Ministry of Health and Social Development of the Russian Federation No. 786n dated December 29, 2008, "On the Procedure for Formation and Approval of the State Assignment for the Provision of High-Tech Medical Care to Citizens of the Russian Federation at the Expense of Federal Budget Appropriations in 2009" (with amendments and additions).

9. Management of Planned Hospitalization in a Multidisciplinary Hospital. Methodological Recommendations No. 2001/144 (approved by the Ministry of Health of the Russian Federation on November 9, 2001).

Table 5. Criteria for choosing the management tactics for a patient with AMD

Appendix B. Physician Action Algorithms

Age-related macular degeneration

Appendix C. Patient Information

Older adults are recommended to undergo a preventive ophthalmological examination, including biomicroscopy of the fundus under conditions of mydriasis (dilated pupil), to detect AMD. In the absence of AMD signs or in the presence of early-stage AMD, subsequent ophthalmological examinations are recommended once a year. The risk of occurrence and progression of the disease to the late stage can be reduced by eliminating risk factors, in particular by quitting smoking, following a diet rich in antioxidants (in particular, lutein and zeaxanthin) and polyunsaturated fatty acids, and maintaining an active lifestyle whenever possible.

In the presence of intermediate or late-stage AMD, or in the presence of risk factors for disease progression, the frequency of doctor visits is determined individually depending on the clinical features and planned management tactics. For self-monitoring of disease progression, patients with intermediate AMD or late-stage AMD in the fellow eye are advised to perform scotometry (Amsler-Marinchev test), which consists of identifying defects in the visual field and distortions of straight lines of the drawn grid while fixing gaze on the central mark.

The clinical picture of AMD, the course and prognosis of the disease, and the diagnostic and treatment methods used vary depending on the stage and form of the disease, and the presence of risk factors for its progression. The chronic course of the disease necessitates regular examinations by an ophthalmologist and, in the case of the wet form of AMD, repeated intravitreal administrations of medicinal products (anti-angiogenic drugs). The risk of complications from intravitreal drug administration is minimal, but it exists.

In the case of significant irreversible reduction in visual functions due to late-stage AMD, visual aids for low vision are available to improve the quality of life.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Not applicable.