1. INTRODUCTION:

Vernal keratoconjunctivitis (VKC) is a chronic, bilateral, seasonally exacerbated allergic inflammation of the ocular surface, primarily affecting the conjunctiva and cornea¹. It is most prevalent in children and adolescents, with a strong male predominance, and often resolves after puberty. The condition is more common in warm, arid regions of Africa, the Middle East, and South Asia, suggesting an environmental trigger in genetically susceptible individuals².

Clinically, VKC manifests as intense ocular itching, photophobia, foreign body sensation, tearing, and mucous discharge. Severe inflammation can result in giant papillae on the upper tarsal conjunctiva, Horner-Trantas dots at the limbus, and corneal complications such as shield ulcers and keratoconus. These symptoms significantly impair quality of life, particularly in school-aged children, and may lead to vision-threatening complications if inadequately treated³.

The pathophysiology of VKC is multifactorial, involving both immediate hypersensitivity (IgE-mediated) and delayed (cell-mediated) immune responses. This complexity poses challenges for effective and sustained treatment⁴. Historically, treatment has relied on supportive measures and pharmacologic agents such as antihistamines, mast cell stabilizers, and corticosteroids. However, long-term steroid use is associated with significant side effects, including glaucoma and cataract formation, necessitating the development of safer and more targeted therapies^5,6.

Recent years have witnessed a paradigm shift in VKC management, with the introduction of immunomodulatory agents such as cyclosporine and tacrolimus, and biologic therapies like omalizumab. These newer agents target the underlying immunopathology more precisely, offering hope for improved disease control with reduced adverse effects. Additionally, innovations in ocular drug delivery systems enhance drug residence time and bioavailability, potentially increasing therapeutic efficacy^7,8.

This review presents a comprehensive overview of the current pharmacological options available for VKC, highlighting their mechanisms, efficacy, safety, and place in therapy. Special emphasis is placed on the transition from conventional treatments to targeted immunomodulators and biologics, representing the future of VKC management.

Figure 1. Types of VKC

2. Pathophysiology and Immunological Basis:

The pathogenesis of vernal keratoconjunctivitis is complex, involving a dual-phase hypersensitivity reaction—both type I (immediate, IgE-mediated) and type IV (delayed, T-cell-mediated) responses. This intricate immune interplay leads to chronic inflammation and structural damage of the conjunctiva and cornea.

2.1 IgE-Mediated Hypersensitivity (Type I):

Upon exposure to environmental allergens (e.g., pollen, dust), sensitized individuals produce IgE antibodies, which bind to high-affinity IgE receptors (FcεRI) on mast cells in the conjunctiva. Re-exposure to allergens leads to cross-linking of IgE, causing mast cell degranulation and the release of histamine, tryptase, prostaglandins, and leukotrienes.

This results in acute symptoms such as itching, redness, tearing, and chemosis within minutes.

2.2 Mast Cells and Eosinophils:

Mast cells play a pivotal role in both early- and late-phase allergic responses. They initiate inflammation and recruit other immune cells through cytokines and chemokines. Eosinophils, a hallmark of VKC, are attracted to the conjunctiva via eotaxin and IL-5 and release major basic protein (MBP), eosinophilic cationic protein (ECP), and leukotrienes, causing tissue damage and epithelial cell toxicity—particularly to the cornea⁹.

2.3 T-Lymphocyte Mediated Immunity (Type IV):

A Th2-dominant immune response underlies the chronic phase of VKC. CD4+ Th2 cells release IL-4, IL-5, and IL-13, promoting IgE production, eosinophil activation, and mucus hypersecretion. This contributes to sustained inflammation, tissue remodeling, and giant papillae formation.

2.4 Cytokines and Chemokines:

Increased levels of IL-4, IL-5, IL-13, TNF-α, and RANTES (regulated upon activation, normal T cell expressed and secreted) are observed in tears and conjunctival tissues of VKC patients. These mediators perpetuate inflammatory cycles and are potential targets for biologic therapy¹⁰.

2.5 Structural Changes and Damage:

Chronic inflammation leads to hypertrophy of the tarsal conjunctiva, limbal infiltration, and corneal involvement (e.g., shield ulcers). Prolonged eosinophilic activity disrupts corneal epithelium and Bowman’s layer, increasing risk for keratoconus and visual loss.

2.6 Genetic and Environmental Interactions:

VKC has been linked to atopic backgrounds and a family history of allergic conditions (asthma, eczema). Environmental factors such as climate, allergens, and UV exposure modulate disease onset and severity¹¹.

3. Clinical Presentation and Diagnosis:

Vernal keratoconjunctivitis (VKC) typically presents with bilateral intense ocular itching, often accompanied by photophobia, foreign body sensation, burning, excessive tearing, and thick, ropy mucous discharge. Blurred vision may occur in moderate to severe cases due to corneal involvement. The most characteristic clinical signs include giant papillae on the upper tarsal conjunctiva (≥1 mm in diameter), giving a cobblestone appearance, and Horner-Trantas dots, which are white limbal nodules composed of eosinophils and degenerated epithelial cells. Limbal hypertrophy with gelatinous thickening and corneal complications such as punctate epithelial erosions or shield ulcers may also be seen in more severe cases¹².

VKC is classified into three main types: (1) Palpebral VKC, which features prominent giant papillae on the upper eyelid; (2) Limbal VKC, more prevalent in individuals with darker skin, characterized by limbal gelatinous thickening and Trantas dots; and (3) Mixed VKC, which displays features of both palpebral and limbal forms (Figure 1). A comparative summary of these clinical types is illustrated in Figure 2.

Figure 2. Classification and Clinical Features of VKC

Diagnosis is mainly clinical but can be challenging due to overlap with other forms of ocular allergy. Differential diagnoses include seasonal allergic conjunctivitis (typically milder and lacking corneal signs), atopic keratoconjunctivitis (which affects older patients and is more chronic), and giant papillary conjunctivitis (associated with contact lens wear or foreign bodies). Infectious conjunctivitis should also be excluded, especially when discharge is purulent or symptoms are unilateral¹³.

4. Conventional Pharmacotherapy:

Conventional pharmacotherapy remains the cornerstone for managing mild to moderate cases of vernal keratoconjunctivitis (VKC). These therapies target symptom relief and control of inflammation through a combination of mast cell stabilizers, antihistamines, NSAIDs, and topical corticosteroids. The choice of agent is often guided by disease severity, response to prior treatment, and safety considerations, especially in pediatric populations. Although effective in many cases, prolonged use—particularly of corticosteroids—requires caution due to the risk of ocular complications such as cataract and glaucoma¹⁴. An overview of conventional pharmacological options, including their mechanisms, benefits, and limitations, is presented in Table 1.

4.1 Mast Cell Stabilizers:

Mast cell stabilizers, such as sodium cromoglycate and nedocromil, are among the first-line agents in VKC management. They act by preventing mast cell degranulation, thus inhibiting the release of histamine and other pro-inflammatory mediators. These agents are more effective when used prophylactically or in mild cases, as their onset of action is delayed and requires regular use over several days or weeks. Limitations include the need for frequent dosing (typically 4–6 times daily) and limited efficacy during acute exacerbations.

4.2 Antihistamines:

Second-generation antihistamines such as olopatadine, ketotifen, and emedastine provide rapid relief from itching and redness. These agents function by blocking H1 receptors and some (e.g., olopatadine and ketotifen) also possess mast cell–stabilizing properties. They are often used in acute phases due to their quick onset of action and convenient twice-daily dosing, which supports better patient compliance. However, they are less effective in addressing chronic inflammation and do not resolve corneal complications¹⁵.

4.3 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs):

NSAIDs like ketorolac and diclofenac reduce ocular inflammation by inhibiting cyclooxygenase enzymes and suppressing prostaglandin synthesis. They can help reduce pain, photophobia, and redness but are generally used as adjuncts. Their long-term use may be limited by potential side effects, such as ocular surface irritation, delayed epithelial healing, and stinging upon instillation¹⁶.

4.4 Corticosteroids:

Corticosteroids, including loteprednol, fluorometholone, and prednisolone acetate, remain highly effective for short-term control of moderate-to-severe VKC, especially during acute flares or when corneal involvement is present. These agents suppress a broad range of inflammatory pathways and offer rapid symptom relief. However, prolonged use is associated with serious side effects, such as ocular hypertension, glaucoma, cataract formation, and increased risk of infection. Therefore, strategies to minimize these risks include using low-potency or soft steroids (e.g., loteprednol), tapering doses, and regular monitoring of intraocular pressure¹⁷.

Table 1. Conventional Pharmacotherapy for VKC

Drug Class	Examples	Mechanism of Action	Advantages	Limitations
Mast Cell Stabilizers	Sodium cromoglycate, Nedocromil	Prevent mast cell degranulation	Good safety profile, preventive therapy	Delayed onset, less effective in acute episodes
Antihistamines	Olopatadine, Ketotifen, Emedastine	H1 receptor antagonism ± mast cell stabilization	Rapid relief of itching	Short duration of action, requires frequent dosing
NSAIDs	Ketorolac, Diclofenac	Inhibit COX → ↓ Prostaglandin synthesis	Anti-inflammatory	Risk of corneal melting (rare), ocular irritation
Corticosteroids	Loteprednol, Fluorometholone, Prednisolone	Broad anti-inflammatory and immunosuppressive	Highly effective during flares	Risk of cataract and glaucoma with long-term use

5. Immunomodulatory Therapy:

As conventional therapies like mast cell stabilizers and antihistamines may prove inadequate in moderate to severe cases of vernal keratoconjunctivitis (VKC), the use of immunomodulatory agents has gained increasing attention. These agents primarily act by suppressing T-cell activation and reducing the production of pro-inflammatory cytokines involved in the Th2-mediated allergic response characteristic of VKC. Topical formulations of Cyclosporine A and Tacrolimus, both calcineurin inhibitors, are commonly employed in patients with persistent or steroid-dependent symptoms. Their ability to provide long-term disease control with minimal systemic absorption makes them particularly useful in pediatric and chronic cases¹⁸. A comparison of key immunomodulatory and biologic agents used in VKC is summarized in Table 2.

5.1 Cyclosporine A:

Cyclosporine A (CsA) is a calcineurin inhibitor that suppresses T-cell activation and the production of inflammatory cytokines like IL-2. It is particularly effective in chronic or steroid-dependent VKC. Topical formulations such as 0.05%, 0.1%, and 0.5% emulsions have been shown to significantly reduce symptoms and minimize the need for corticosteroids. Although some patients experience a transient burning sensation upon application, CsA is generally well tolerated and safe for long-term use in children and adolescents with persistent or moderate-to-severe VKC¹⁹.

5.2 Tacrolimus:

Tacrolimus, another calcineurin inhibitor, is more potent than cyclosporine and is effective in refractory VKC cases. It works by inhibiting T-cell activation and cytokine release, similar to CsA, but at lower concentrations. Topical tacrolimus (0.03% or 0.1% ointment) has demonstrated excellent outcomes in reducing inflammation and restoring ocular surface integrity. Though not officially approved in many regions for ophthalmic use, it is commonly used off-label, particularly in pediatric VKC. Tacrolimus is generally well tolerated, with occasional reports of local irritation or burning. Systemic use is rare and reserved for very severe or multi-system atopic conditions²⁰.

6. Emerging Biologic Therapies:

6.1 Anti-IgE Therapy (Omalizumab):

The rationale for using omalizumab, a recombinant humanized monoclonal antibody against IgE, in VKC stems from the disease’s strong association with type I hypersensitivity reactions. VKC patients often have elevated total and specific serum IgE levels, and IgE plays a critical role in mast cell activation and early-phase allergic responses. By binding to free IgE, omalizumab prevents its interaction with FcεRI receptors on mast cells and basophils, thereby reducing allergic inflammation.

Although omalizumab is not officially approved for VKC, several case reports and small-scale clinical studies have reported favorable outcomes in severe, refractory cases, particularly in patients unresponsive to conventional and immunosuppressive therapy. It has shown to reduce conjunctival inflammation, itching, and steroid dependency in some pediatric cases. However, its use remains off-label, and data from large, controlled trials are lacking²¹.

Despite its therapeutic potential, limitations include high cost, subcutaneous route of administration, and the need for regular injections (every 2–4 weeks). Moreover, its use is typically limited to the most severe and steroid-resistant VKC cases due to safety, monitoring, and access concerns.

6.2 Other Investigational Agents:

Other biologic agents under investigation include IL-5 inhibitors like mepolizumab and IL-4/IL-13 pathway blockers such as dupilumab. These are based on the understanding that eosinophils, Th2 lymphocytes, and related cytokines (IL-5, IL-4, IL-13) are central to VKC pathogenesis²².

Mepolizumab, an anti-IL-5 monoclonal antibody, reduces eosinophil activation and survival, making it a potential therapeutic candidate in eosinophilic-dominant VKC. Dupilumab, which blocks the shared receptor component of IL-4 and IL-13, has demonstrated success in atopic dermatitis and asthma and is being explored for ocular allergy and VKC. While these agents have not yet been approved for VKC, early evidence supports their immunological targeting as promising for future personalized therapy.

Nevertheless, robust clinical data are still needed, and concerns regarding systemic immunosuppression, high cost, and long-term safety in pediatric populations must be addressed before these can be integrated into mainstream practice²³.

7. Drug Delivery Advances in VKC Therapy:

Conventional eye drops in VKC face challenges such as rapid tear turnover, low corneal penetration, and the need for frequent dosing. Recent innovations in ocular drug delivery systems aim to enhance drug residence time, bioavailability, and patient compliance, while minimizing side effects.

Nanocarriers, such as lipid-based nanoparticles, polymeric nanoparticles, and dendrimers, offer controlled and sustained release of anti-inflammatory or immunosuppressive agents. They can improve drug stability and penetration across ocular tissues while reducing systemic exposure. Cyclosporine-loaded nanoparticles, for example, have shown improved tolerability and efficacy compared to conventional formulations²⁴.

Liposomal eye drops are biocompatible and provide a sustained-release mechanism that can be tailored for hydrophilic or lipophilic drugs. Liposomes have been investigated for delivering tacrolimus and cyclosporine with promising results in preclinical studies.

Mucoadhesive polymers, such as chitosan and hyaluronic acid-based formulations, adhere to the ocular surface and prolong the drug’s contact time, potentially reducing the frequency of administration. These formulations may improve patient adherence, especially in pediatric VKC cases²⁵.

Despite these advances, barriers such as regulatory approval, formulation scalability, ocular irritation potential, and cost still hinder the widespread clinical adoption of advanced delivery systems. Further translational research and clinical trials are needed to validate their efficacy and safety in VKC patients.

8. Comparative Efficacy and Treatment Algorithms:

In VKC, therapeutic choice depends on disease severity, duration, and individual patient response. Mild cases often respond well to topical antihistamines or mast cell stabilizers, which are safe for long-term use but less effective during acute exacerbations. Moderate cases may require a combination of dual-action agents and short-term topical corticosteroids. For severe or refractory VKC, immunomodulators such as cyclosporine A or tacrolimus are effective steroid-sparing alternatives.

Comparatively, tacrolimus appears more potent than cyclosporine, especially in treatment-resistant cases, but both have favorable safety profiles for long-term use. In patients unresponsive to topical therapies, biologic agents such as omalizumab may be considered as off-label options in highly selected cases²⁶.

A stepwise management approach (Table 3) is recommended: starting with antihistamines or mast cell stabilizers for mild cases, adding topical steroids or NSAIDs during flares, and progressing to immunomodulators or biologics for persistent or steroid-dependent disease. Regular follow-up and IOP monitoring are essential when corticosteroids are used.

Personalized therapy, based on immune profiling, symptom patterns, and treatment response, represents the ideal strategy. Pediatric compliance, disease seasonality, and prior treatment history should guide therapeutic decisions to balance efficacy and safety²⁷.

Table 3. Stepwise Management Algorithm for VKC

Severity Level	First-Line Therapy	Second-Line	Third-Line / Rescue
Mild	Lubricants + Cold compresses + Mast cell stabilizers	Topical dual-acting antihistamines	—
Moderate	Add topical corticosteroids (short-term)	NSAIDs ± Cyclosporine A	—
Severe	Topical steroids (pulse), Cyclosporine A or Tacrolimus	Consider Omalizumab or Dupilumab (off-label)	Systemic immunosuppression (rarely needed)

9. Challenges and Future Directions:

Despite recent advancements, several challenges remain in the long-term pharmacological management of VKC. One of the primary concerns is the long-term safety of immunosuppressants and biologics in children, who represent the majority of VKC patients. While agents like cyclosporine and tacrolimus have shown favorable safety in chronic use, more data are needed, especially regarding growth, immunity, and ocular development in children²⁸.

Another challenge is the lack of large, multicenter randomized controlled trials (RCTs) for newer therapies. Most evidence comes from small case series or observational studies, which limit the generalizability of findings. Without robust comparative data, standardization of treatment protocols remains difficult.

The cost and accessibility of biologics and advanced drug delivery systems also pose barriers, particularly in low- and middle-income countries where VKC is more prevalent. In addition, pediatric formulation availability and patient compliance with topical therapies remain concerns that can affect long-term outcomes²⁹.

Finally, there is a pressing need for evidence-based guidelines and treatment algorithms, ideally stratified by disease severity and age group. Future research should focus on developing biomarker-based personalized therapies, enhancing drug delivery technologies, and conducting long-term safety trials to support rational use of biologics and immunomodulators in VKC³⁰.

10. CONCLUSION:

Vernal keratoconjunctivitis (VKC) is a chronic, recurrent, and often vision-threatening ocular allergy that significantly impacts the quality of life, especially in children and adolescents. While conventional therapies such as mast cell stabilizers, antihistamines, NSAIDs, and corticosteroids remain the cornerstone of management, their limitations—particularly with long-term use—underscore the need for more effective and safer alternatives. The introduction of immunomodulatory agents like cyclosporine A and tacrolimus has transformed the treatment landscape, offering long-term control with reduced dependence on corticosteroids. More recently, biologic agents such as omalizumab and investigational therapies targeting interleukin pathways have emerged as promising options for refractory VKC, though their widespread use is currently limited by cost, availability, and lack of large-scale clinical trials. Advances in ocular drug delivery systems, including nanocarriers and mucoadhesive formulations, offer new opportunities to enhance drug efficacy, prolong retention time, and improve patient compliance—particularly crucial in pediatric populations. Looking forward, the future of VKC management lies in personalized, immune-targeted approaches supported by robust clinical evidence and safer, more patient-friendly formulations. Multidisciplinary collaboration, long-term safety studies, and accessible treatment guidelines are essential to ensure optimal outcomes and improve the standard of care for VKC worldwide.

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Received on 07.08.2025 Revised on 27.08.2025

Accepted on 11.09.2025 Published on 11.10.2025

Available online from October 25, 2025

Res.J. Pharmacology and Pharmacodynamics.2025;17(4):304-310.

DOI: 10.52711/2321-5836.2025.00047

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

Agent	Type	Mechanism	Efficacy	Concerns
Cyclosporine A	Calcineurin inhibitor	Blocks T-cell activation → ↓ IL-2	Proven in long-term VKC	Local irritation, slow onset
Tacrolimus	Calcineurin inhibitor	More potent than CsA, similar mechanism	Effective even in refractory VKC	Burning sensation, limited formulations
Omalizumab	Anti-IgE biologic	Binds free IgE → ↓ mast cell degranulation	Effective in severe cases	High cost, off-label in VKC
Dupilumab	IL-4/IL-13 blocker	Inhibits Th2 cytokine pathway	Promising in atopic/VKC overlap	Not yet widely studied in VKC