New Applications of Targeted Therapy in Family Medicine Practice for the Treatment of Complications of Inflammatory Diseases of the Anterior Segment of the Eye

Inflammatory eye diseases are one of the most significant challenges in ophthalmology due to their high prevalence, frequent occurrence in people of working age, and the risk of disabling consequences. According to epidemiological studies, the frequency of patient visits for inflammatory ophthalmic conditions is 23% and ranks second after refractive and accommodative disorders (40.0% of visits). It accounts for about 40% of outpatient visits and approximately 80% of cases of temporary disability.

Dry eye disease (DED), or dry keratoconjunctivitis, is a very common pathological condition that adversely affects quality of life. Although the disease is moderately severe in most patients, in the most severe cases, corneal ulcers may develop and conjunctival scarring may occur. It should also be noted that the course of DSE makes wearing contact lenses difficult and worsens the prognosis for refractive laser surgery.

On June 29, a scientific and practical conference titled “Modern Academic Knowledge in the Practice of the General Practitioner—Family Physician (Ukrainian Professional School with International Participation)” was held, during which current issues in modern medicine were discussed: providing care to patients with non-alcoholic fatty liver disease, atrial fibrillation, irritable bowel syndrome, as well as the treatment of eye injuries, glaucoma, and inflammatory diseases of the anterior segment of the eye.

The head of the Department of Ophthalmology at the P.L. , Corresponding Member of the National Academy of Medical Sciences of Ukraine, Honored Physician of Ukraine, Doctor of Medical Sciences, Professor, and Chairman of the Board of the NGO “Association of Pediatric Ophthalmologists and Optometrists of Ukraine,” Serhiy Oleksandrovych Rykov.

Dry eye syndrome is often referred to as a disease of civilization. Its prevalence is approximately 9–18% among the population of highly developed countries worldwide. Over the past decades, the incidence of dry eye syndrome has increased 4.5-fold.

The condition is more common in women than in men—accounting for 69.7% of cases. Among ophthalmology patients under 50 years of age, it is diagnosed in 12% of cases, and in patients over 50 years of age, in 67% of cases. Among patients with glaucoma, the prevalence of dry eye disease is approximately 10–12% and is on the rise.

At the TFOS DEWS II workshop on dry eye syndrome, it was determined that dry eye disease is a multifactorial disorder of the ocular surface characterized by a loss of tear film homeostasis, accompanied by ocular symptoms in which tear film instability, hyperosmolarity, inflammation, and damage to the ocular surface, as well as neurosensory abnormalities, play an etiological role.

The new definition of dry eye disease highlights the characteristics and mechanisms of this condition. Loss of tear film homeostasis plays a key role in the development of dry eye disease, accompanied by changes in its chemical composition and functional imbalance, which leads to damage to the ocular surface and the development of disease symptoms.

Tear film instability and hyperosmolarity, inflammation and damage to the ocular surface, and neurosensory abnormalities are also etiological factors in dry eye disease.

Neurosensory abnormalities develop through the pathophysiological pathways of dry eye syndrome. Corneal nociceptors, which transmit somatosensory information about “pain” to the central nervous system, are susceptible to sensitization by repeated physiological stimulation or pathological stimuli, such as hyperosmolarity/inflammation. Hyperosmolarity of the tear film, either directly or by initiating the inflammatory process, also damages the ocular surface and is a characteristic feature of the disease.

Thus, all these complications lead to a cycle of events known as a vicious cycle, which explains why damage to the ocular surface is initiated and subsequently repeated in DKS.

It has been established that the causes of SJS may include systemic diseases and syndromes associated with reduced tear production. These include autoimmune diseases: primary Sjögren’s syndrome, secondary Sjögren’s syndrome in rheumatoid arthritis, systemic lupus erythematosus, nodular periarteritis, systemic scleroderma, polymyositis, dermatomyositis, primary biliary cirrhosis, Wegener’s granulomatosis, graft-versus-host disease, and immune processes following radiation exposure to the head and neck. HSO may develop as a result of diseases of the hematopoietic and reticuloendothelial systems: rheumatoid arthritis combined with splenomegaly and neutropenia (Felty’s syndrome), malignant lymphoma, lymphosarcoma, hemolytic anemia, thrombocytopenic purpura, hypergammaglobulinemia, macrogammaglobulinemia. Causes of XSO may include endocrine dysfunctions (menopausal syndrome, endocrine ophthalmopathy, hypothyroidism, diabetes mellitus), kidney diseases (renal tubular acidosis, diabetes insipidus), debilitating infectious diseases (typhoid fever, cholera, leprosy, HIV infection, starvation, vitamin E and B12 deficiency). Diseases of the skin and mucous membranes leading to combined tear and mucus insufficiency (pemphigus, toxic epidermal necrolysis, neurodermatitis, rosacea, congenital ichthyosis, dry ichthyosiform erythroderma), and pregnancy are also causes of XSO. However, the most significant of these are Sjögren’s syndrome, ocular pemphigoid, endocrine ophthalmopathy, and climacteric syndrome.

Pathological conditions of the eye and surgical interventions may be accompanied by a decrease in the stability of the tear film. These include corneal and conjunctival scars of various origins, leading to impaired congruence of the surfaces of the eyeball and eyelids (ankyloblephron, symblepharon, pterygium, pemphigus conjunctivae, stage IV burn disease); neuroparalytic keratitis; lagophthalmos, exophthalmos of various origins, buphthalmos, keratoconus; post-infectious allergic conditions; impaired drainage of tear fluid through the excretory pathways, chronic dacryocystitis; dysfunction of the lacrimal gland or its absence (aplasia, hypoplasia). The most significant of these are refractive eye surgeries, lagophthalmos, and neuroparalytic keratitis.

It should be noted that certain medications or their prolonged use can lead to reduced tear production or disruption of the tear film’s stability. These include β-blockers (propranolol, atenolol, metoprolol); α1- and α2-adrenergic blockers (clonidine, prazosin); sympatholytic agents (reserpine); centrally acting antihypertensives (methyldopa); diuretics (indapamide); antiarrhythmic drugs (disopyramide, mexiletine); anticholinergic agents (atropine and its analogs); antihistamines (diphenhydramine); antidepressants (amitriptyline, imipramine); antiparkinsonian anticholinergic agents (trihexyphenidyl, biperiden). Additionally, emetics and antiemetics (metoclopramide); minor tranquilizers (chlordiazepoxide, diazepam, nitrazepam); phenothiazine antipsychotics (thioridazine, haloperidol); antimetabolites (methotrexate, cytarabine); uterine agents (ergotamine); thiazide diuretics (hydrochlorothiazide); retinoids (isotretinoin, acitretin); salicylates (acetylsalicylic acid); estrogenic steroids (estradiol); oral contraceptives (Ovidon, Logest, Bisecurin, and other combined estrogen-progestin preparations).

Currently, dry eye disease is classified into the following types: aqueous deficiency, associated with increased evaporation, and a mixed type that combines aqueous deficiency and evaporation.

To establish a diagnosis and prescribe optimal treatment, it is necessary to ask the patient a series of questions:

• How severe is the discomfort in your eyes?
• Do you experience dry mouth or swollen glands?
• How long have your symptoms lasted, and have you experienced any other symptoms?
• Do you experience blurred vision, and does it clear up after blinking?
• Are the symptoms or redness more severe in one eye compared to the other?
• Do you experience itching, eye swelling, crusting on the eyelashes, or mucus discharge?
• Do you wear contact lenses?
• Have you been diagnosed with any inflammatory conditions (including recent respiratory infections), or are you taking any medications?

A thorough examination of the anterior segment and differential diagnosis are then necessary, especially when patients have given affirmative answers.

In addition, it is important to identify risk factors such as smoking, use of certain medications, and contact lens wear, and to assess symptoms (DEQ-5 ≥ 6 or OSD ≥ 13).

Homeostasis markers are used for screening: a non-invasive fluorescein test, tear film break-up time ≤ 10 seconds, osmolarity ≥ 308 mOsm/L for either eye or a difference between the two eyes ≥ 8 mOsm/L, and staining of the ocular surface > 5 spots on the cornea, > 9 spots on the conjunctiva or eyelids (≥ 2 mm in length and ≥ 25% of the width). Tests are performed to classify subtypes and determine the severity in cases of evaporation and aqueous deficiency.

After diagnosing the disease, a stepwise treatment algorithm must be followed: restore ocular surface homeostasis, starting with simple therapeutic methods and gradually progressing to more complex ones. For each patient category, one or several options may be considered simultaneously within a specific stage, depending on the severity of dry eye syndrome.

The first pathogenetic type of dry eye syndrome is characterized by a decrease in the production of various components of the tear film. A decrease in total tear production leads to thinning of the aqueous layer of the tear film, agglutination of lipids with mucins, and the formation of unmoistened areas on the corneal surface.

The second pathogenetic type of dry eye syndrome is caused by a decrease in the stability of the precorneal film. Exogenous factors lead to its thinning due to active evaporation. A decrease in mucin secretion by the epithelial cells of the conjunctiva and cornea is observed, accompanied by the flattening of the cilia of the anterior epithelial membrane. A decrease in mucopolysaccharide production is characterized by impaired interaction of mucins with the aqueous layer of the tear film and a reduction in its thickness.

Treatment involves eyelid hygiene, pharmacological stabilization of the tear film, stimulation of tear production, reduction of tear film evaporation, stimulation of corneal and conjunctival epithelial regeneration, and general restorative therapy.

It should be emphasized that eyelid hygiene plays an important role in the prevention of blepharitis, which is the main reason for the cancellation of cataract surgery and laser refractive surgeries. It has been proven that practicing eyelid hygiene 10 days prior to surgery reduces the risk of cancellation by 2.5 times and lowers the risk of postoperative complications.

The third pathogenetic type of XSO is caused by a combination of a deficiency in the production of the main components of the tear film and a simultaneous exogenous disruption of its stability.

It may occur as a result of conjunctival scarring following the use of antiglaucoma eye drops, as well as in patients using miotic agents. For its diagnosis, it is essential to perform a conjunctival biopsy and examine the biopsy specimen, which allows for the identification of subepithelial bullae and subepithelial fibrosis in ocular pemphigoid.

To control inflammation in ocular pemphigoid, it is preferable to use nonsteroidal anti-inflammatory drugs: doxycycline in mild cases, and the more potent cyclophosphamide or azathioprine in refractory cases. Eyelid hygiene is also performed, along with intensive lubrication of the eyeball (4–10 times daily) using pharmacological stabilization of the tear film, stimulation of tear production, and reduction of tear film evaporation; corneal protectors are applied, occlusion of the lacrimal puncta/lacrimal ducts, and cauterization of the lacrimal puncta. Correction of trichiasis or eyelid inversion is performed with caution, as there is a risk of exacerbating inflammation. This also applies to the use of corticosteroids and wearing contact lenses.

HSO in endocrine ophthalmopathy also belongs to the mixed (third) pathogenetic type, which is caused by a combination of a deficiency in the production of the main components of the tear film with a simultaneous exogenous disruption of its stability. For diagnosis, immunofluorescence is used to detect antigen-antibody complexes in the conjunctival basement membrane, along with an evaluation of the immune system. Treatment involves alleviating inflammation, which is achieved by prescribing nonsteroidal anti-inflammatory drugs. Orbital decompression and surgeries on the extraocular muscles are performed. In addition, eyelid hygiene, intensive lubrication of the eyeball, use of corneal protectors, occlusion of the lacrimal punctum/lacrimal ducts, and systemic glucocorticoid or immunosuppressive therapy (cyclophosphamide, methotrexate, azathioprine) are necessary.

Dry eye disease very often develops with contact lens use, associated with mechanical or toxic effects of contact lenses or lens care products, infectious diseases, eye conditions (epithelial defects, erosion, corneal dystrophy, post-traumatic or post-surgical conditions of the cornea, diseases of the eyelids and conjunctiva, and reduced or impaired tear production). This is exacerbated by improper lens selection, undetected pathological changes in the cornea, failure to adhere to follow-up care, hygiene rules, and the recommended lens wear duration, the occurrence of relative hypoxia due to restricted oxygen supply to eye tissues, changes in metabolic processes, and systemic diseases (diabetes, vitamin deficiency), as well as the use of medications whose side effects include deposits on the lenses, reduced tear production, and impaired adaptation to contact lenses.

It is important to remember that the use of Paragon overnight lenses can lead to complications such as corneal edema, central and peripheral staining of the corneal epithelium, hypo- or hypercorrection of refractive errors, and infectious and toxic-allergic complications.
Therefore, their use is contraindicated in cases of corneal inflammation or infectious diseases, severe dry eye syndrome, keratoconus or keratoglobus, cataracts, and glaucoma. The use of overnight lenses is also not recommended in cases of corneal astigmatism of 1.75 diopters or higher, various eyelid diseases, upper eyelid rigidity, lagophthalmos, decreased corneal sensitivity, allergic reactions of the eye to the lens material or to the chemical components of lens care products, and various eye injuries or abnormalities affecting the cornea, conjunctiva, or eyelids.Therefore, for preventive purposes, regular medical check-ups are necessary for patients who use contact lenses, and measures must be taken to ensure the timely resolution of potential complications at the earliest signs of their occurrence, such as changing the diameter or base curve of the lenses, changing the type of lenses, using toric lenses instead of spherical ones, changing cleaning and disinfecting solutions, and reducing the wearing time of the lenses. It is recommended to carefully monitor the correct selection of lens parameters and to use soft contact lenses with a scheduled replacement schedule, which reduces the risk of complications.The development of severe complications is often associated with patients seeking medical attention too late. Patients who wear contact lenses should always be instructed about these consequences. Patients should be advised on the use of cosmetics: makeup should be applied after inserting the lenses; avoid applying a thick layer of makeup to the eyelids; and replace mascara every three months, as microorganisms are present in cosmetics, despite the presence of disinfectants and the cleanliness of the container.It is particularly important to explain to patients in detail the importance of adhering to the correct lens-wearing regimen, maintaining hygienic conditions during use, and cleaning the lenses promptly. Studies have shown that approximately 30–50% of patients do not follow lens care guidelines (due to ignorance, carelessness, forgetfulness, etc.), and about 30% of patients make mistakes when caring for their lenses.During flu and acute respiratory infection (ARI) outbreaks, experts recommend closely monitoring contact lens use and immediately stopping wearing them if you become ill.

Given the growing number of patients with tear film dysfunction, the range of medications and physiotherapeutic approaches prescribed for the treatment of dry eye disease is expanding.

Currently, for all forms of dry eye syndrome, it is necessary to prescribe agents that provide lubrication of the ocular surface. According to the recommendations of the Buckinghamshire Healthcare NHS Trust of the UK National Health Service, the first-line treatments in the range of moisturizing agents for dry eye syndrome are 0.4% eye drops or ointments based on hyaluronic acid or its derivatives (sodium hyaluronate) without preservatives.

Sodium hyaluronate-based drops and ointment are represented by the Gilays® product line, which includes Gilays® solution and Gilays® Kea ointment (Kyiv Vitamin Plant JSC). These preparations do not affect the normal conjunctival epithelium, do not impair the secretory functions of goblet cells, and do not disrupt intercellular interactions.

Due to their high adhesion to the mucin component of the tear film, Gilays® and Gilays® Kea do not wash off the ocular surface during blinking and do not affect visual acuity. Due to their high viscosity, they maintain the tear film in the open eye, while a decrease in viscosity during blinking contributes to a comfortable sensation when the eyes are closed. In cases of ocular surface damage, Gilays® and Gilays® Kea reduce squamous metaplasia, improve goblet cell expression, and enhance epithelial cell morphology.

Hylase® is a 0.4% ophthalmic solution of high-molecular-weight sodium hyaluronate. Gilaise® restores the layers of the tear film, ensures prolonged retention on the ocular surface by forming a viscoelastic gel thanks to a phosphate buffer, has a physiological pH of 7.3, and a high tolerability and safety profile.

Gilaise® is an ideal natural lubricant with high mucoadhesive and rheological properties. It has anti-inflammatory and antioxidant effects and promotes the regeneration and healing of corneal defects. Thanks to these properties, Gilays® improves tear film stability and ensures eye surface comfort, helping to eliminate irritation, dryness, burning, and the sensation of a foreign body in the eyes caused by environmental factors such as wind, sun, dry air, salt water, smoke, excessive light, air conditioning, heating, prolonged computer use, or in cases of eye surgery, conjunctivitis, or frequent or prolonged contact lens use.

The Hylaise® bottle is equipped with an innovative, patented multi-dose push-type ophthalmic dispenser (OSD) that protects the solution from potential contamination by harmful bacteria. Thanks to this, the solution remains sterile for 120 days after first use.

In turn, Gilays® Kea is a sterile ophthalmic isotonic ointment containing 0.4% sodium hyaluronate. It possesses unique viscoelastic and hygroscopic properties (retains a volume of water 1,000 times greater than its own), exerts anti-inflammatory and antioxidant effects, stimulates the regeneration of the corneal and conjunctival epithelium following mechanical injury as early as the 7th day, reducing the defect area from 9.83 ± 8.50 mm² to 0.02 ± 0.06 mm². Gilays® Kea promotes the migration and proliferation of corneal epithelial cells, as well as water binding, thereby counteracting dehydration.

The viscous texture of Gilays® Kea ointment ensures long-lasting retention on the eye surface (for 6 hours or more) and provides moisturizing and protective effects even during sleep. An important characteristic of Gilays® Kea ointment is its isotonicity, which helps reduce the hyperosmolarity of tears—a necessary factor in the treatment of dry eye disease.

Gilaise® Kea ointment is intended to relieve symptoms of dry eye during sleep and in cases of lagophthalmos, traumatic corneal injuries, and the effects of keratitis. Its composition ensures retention on the eye’s surface, and sodium hyaluronate forms a protective film on the cornea’s surface, providing protection and hydration.

To combat infectious complications of various origins, Tobiflamin (Kyiv Vitamin Plant JSC) is prescribed, which contains the antibacterial and anti-inflammatory components tobramycin and dexamethasone. Tobramycin is a highly active, fast-acting bactericidal aminoglycoside antibiotic that is active against Gram-positive bacteria (Staphylococcus aureus, Staphylococcus epidermidis, other coagulase-negative Staphylococcus species, Streptococcus pneumoniae, other Streptococcus species) and Gram-negative microorganisms (Acinetobacter spp., Citrobacter spp., Enterobacter spp., Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Moraxella spp., Morganella morganii, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens). The mechanism of action of tobramycin involves the inhibition of bacterial ribosomal function; it has been a reliable treatment for superficial ocular infections for many years and is also used as the gold standard in clinical trials where a new drug must be compared with a well-established agent.

The second component of Tobiflamin—dexamethasone—is a well-known corticosteroid anti-inflammatory agent that exerts its effect by inhibiting cyclooxygenases, reducing the release of pro-inflammatory cytokines, and preventing the adhesion of circulating leukocytes to the vascular endothelium.

The indication for the use of Tobiflamin is ocular inflammation in patients for whom steroid use is indicated and who have a superficial bacterial eye infection or a risk of developing one. Such conditions are typically observed following surgical procedures or may be caused by infection, a foreign object entering the eye, or trauma. The use of Tobiflamin allows for the elimination of bacterial infection or the prevention of its development, as well as the minimization of associated inflammatory changes, which promotes faster recovery and restoration of all functions of the affected eye.

Tobiflamin is instilled as 1 or 2 drops into the conjunctival sac every four hours. It is approved for use in children from one year of age and in adult patients.

Prepared by Tetiana Chystyk