Vernal keratoconjunctivitis (VKC) is an allergic conjunctival disease primarily involving a type I allergic reaction, with proliferative changes in the conjunctiva (giant conjunctival papillae, limbal proliferation) 7). In the Japanese Guidelines for Allergic Conjunctival Disease, 3rd Edition, allergic conjunctival disease (ACD) is defined as “an inflammatory disease of the conjunctiva primarily involving a type I allergic reaction, accompanied by subjective symptoms and objective findings triggered by antigens,” and VKC is classified as a severe type with conjunctival proliferative changes and corneal lesions 7).
The term “vernal” means spring, and it was named because it tends to worsen in spring. However, in practice, many cases follow a perennial course, and the pathophysiology involves not only type I allergy but also a type IV hypersensitivity reaction driven by CD4-positive type 2 helper T cells (Th2 cells).
Allergic conjunctival diseases are classified into the following four types 7).
Allergic conjunctivitis (AC): No proliferative changes in the conjunctiva. Subdivided into seasonal (SAC) and perennial (PAC).
Atopic keratoconjunctivitis (AKC): Chronic ACD accompanied by atopic dermatitis on the face. Often involves conjunctival fibrosis and corneal neovascularization and opacification.
Vernal keratoconjunctivitis (VKC): Proliferative ACD. Some cases are complicated by atopic dermatitis. Presents with various corneal lesions such as corneal epithelial disorders, corneal erosion, persistent epithelial defects, shield ulcers, and corneal plaques.
According to a nationwide survey cited in the third edition of the Japanese guidelines, the prevalence of allergic conjunctival diseases overall has reached 48.7%, a marked increase compared to the 1993 Ministry of Health field survey (15–20%)7). The breakdown by disease type is as follows7).
The age distribution of VKC in a 2017 national survey showed the highest peak in the 20s, with another significant peak during school age, predominantly in boys around 10 years old 7). The age of onset ranges from 5 to 25 years, with a peak at 10–12 years. In most cases, symptoms naturally resolve by adolescence, but about 12% of patients continue to have symptoms into adulthood. Although more common in boys, the gender difference narrows with age.
In Japan, symptoms tend to worsen during the hot and humid summer and in spring when cedar and cypress pollen are dispersed. However, because house dust and mites are common causative antigens, many cases follow a perennial course. Furthermore, in an epidemiological survey by the Japanese Ophthalmological Society’s Allergy Eye Disease Research Group from 1993 to 1995, allergic conjunctivitis overall peaked in the teens and decreased with age. In contrast, the 2017 survey showed a pattern with the highest peak in the 40s and a smaller peak in the teens 7). This change is thought to reflect changes in antigen exposure, improvements in diagnostic techniques, and shifts in population demographics.
VKC is classified into three types based on the location of clinical findings.
Palpebral type: Characterized by cobblestone-like giant papillae on the upper tarsal conjunctiva. This is the most common type. It is often accompanied by punctate keratopathy, corneal ulcers, and mucous discharge.
Limbal type: Characterized by gelatinous limbal elevations and Horner-Trantas dots. Mild cases may be missed without fluorescein staining.
Mixed type: Features of both palpebral and limbal types.
Many patients have a personal or family history of atopy. In a next-generation sequencing (NGS) analysis of monozygotic twins and their father, HLA-DQB105:01, HLA-DRB101:01:01, and HLA-A*32:01:01 were associated with VKC 2). However, a clear correlation with a single causative genetic locus has not been established.
QWhat is the difference between VKC and atopic keratoconjunctivitis (AKC)?
A
VKC typically develops around age 10, with cobblestone giant papillae on the upper tarsal conjunctiva, and often resolves spontaneously after puberty. In contrast, AKC develops in the 20s to 50s, is associated with atopic dermatitis, follows a chronic course, and tends to cause conjunctival shortening, symblepharon, and corneal opacity. While VKC is often associated with sensitization to house dust and mites, AKC is characterized by a higher eosinophil positivity rate in conjunctival scrapings and markedly elevated serum IgE. However, cases of VKC complicated by atopic dermatitis tend to be more severe, and differentiation between the two can be difficult.
Giant papillae in the palpebral conjunctival type of vernal keratoconjunctivitis
Mehta JS, et al. Diagnosis, Management, and Treatment of Vernal Keratoconjunctivitis in Asia: Recommendations From the Management of Vernal Keratoconjunctivitis in Asia Expert Working Group. Front Med (Lausanne). 2022;9:882240. Figure 2. PMCID: PMC9376221. License: CC BY.
This shows the palpebral conjunctival type, a clinical subtype of vernal keratoconjunctivitis, characterized by large cobblestone-like papillae on the upper palpebral conjunctiva. This corresponds to the cobblestone giant papillae discussed in the section “2. Main Symptoms and Clinical Findings.”
VKC is characterized by a stronger complaint of eye pain compared to other allergic conjunctival diseases. Patients often report eye pain rather than itching or foreign body sensation, and in severe cases, it can lead to decreased vision 7).
Itching: This is the most diagnostically specific subjective symptom in allergic conjunctival diseases. The GL 3rd edition classifies the intensity of ocular itching as “severe,” “moderate,” or “mild,” and severe itching is an important diagnostic criterion for VKC 7).
Eye pain: This is particularly severe in VKC and is associated with corneal lesions.
Mucoid discharge: VKC may present with yellow, viscous discharge that is stringy in nature.
Photophobia and tearing: These increase with the progression of corneal complications.
Foreign body sensation: Caused by giant papillae contacting the cornea.
Blurred vision: Occurs when corneal epithelial damage or corneal plaques extend to the pupillary area.
In highly active states, patients may be unable to move upon waking due to severe blepharospasm and mucous discharge, a condition called “morning misery.” This significantly impacts school and daily life and can lead to school refusal.
The GL 3rd edition organizes the specificity of clinical symptoms and lists giant papillae, limbal proliferation, and shield ulcer as objective findings with “high specificity” 7). These are core findings for diagnosing VKC.
Findings of the Palpebral Type
Cobblestone giant papillae: Flat papillae larger than 1 mm in diameter are densely packed on the upper tarsal conjunctiva, presenting a cobblestone appearance. In the GL 3rd edition, papillae with a diameter of 1 mm or more are defined as giant papillae.
Indicators of activity: The degree of hyperemia, mucoid discharge between papillae, and fluorescein staining of the papillary tips serve as indicators of disease activity.
Observation method: Eversion of the upper eyelid is essential, and evaluation is performed using a slit-lamp microscope.
Findings in the bulbar type
Horner-Trantas spots: White spots seen at the corneal limbus, consisting of degenerated epithelial cells and eosinophil aggregates. In the GL 3rd edition, they are classified as mild, moderate, or severe based on the number of spots around the entire limbus.
Limbal gelatinous thickening: The corneal limbus becomes gelatinously swollen. Limbal papillae may coalesce.
Pseudogerontoxon: In cases with severe limbal inflammation, an arcus senilis-like opacity may remain in the peripheral superficial stroma 7).
Shield ulcer: An oval shallow ulcer forms in the superior cornea. Direct cellular damage to the corneal epithelium by eosinophil-derived major basic protein (MBP) and eosinophil cationic protein (ECP) underlies the pathology.
Corneal plaque: A plaque containing fibrin and mucus deposits on the base of the shield ulcer. This can delay epithelial regeneration.
Histological examination of the cornea in the cicatricial stage of VKC reveals epithelial hyperplasia, loss of Bowman’s layer, stromal hyalinization, and neovascularization3). Immunohistochemically, ABCG2 (a limbal stem cell marker) is lost while p63 remains, suggesting partial dysfunction of limbal stem cells3). This finding is important for prognosis assessment after corneal transplantation (DALK or PKP).
A rare complication is tarsal conjunctival keratinization. Bilateral tarsal conjunctival keratinization was first reported in a VKC patient with long-standing disease (onset in childhood, over 20 years), and was managed without recurrence for 4 years after lesion excision and conjunctival autograft 4). In the same case, corrected visual acuity of 0.8 (20/25) was achieved with scleral lens (PROSE) wear 4).
QWhy does shield ulcer occur?
A
MBP (major basic protein) and ECP (eosinophil cationic protein) released from eosinophils cause direct cellular damage to the corneal epithelium. Mechanical friction from giant papillae adds to this, forming an oval shallow ulcer (shield ulcer) in the upper cornea. When fibrin and mucus deposit on the ulcer base, it becomes a corneal plaque, hindering epithelial regeneration. During the active phase, MBP and ECP have antibacterial effects, making infection less likely; however, indiscriminate use of steroids during remission increases the risk of bacterial keratitis, so caution is needed.
VKC cannot be explained solely by simple IgE-mediated type I allergy. CD4-positive Th2 cell-driven type IV hypersensitivity plays an important role. In animal model studies, involving type I allergy alone did not induce conjunctival eosinophil infiltration, whereas involving Th2 cells induced strong conjunctival eosinophil infiltration. This finding indicates that Th2 cells play a central role in the pathogenesis of VKC.
Th2 cells: Produce cytokines such as IL-4, IL-5, and IL-13, promoting eosinophil recruitment and activation.
Eosinophils: Consistently detected in conjunctival scrapings. MBP and ECP have direct cytotoxicity to corneal epithelium. A correlation between corneal damage, a severity indicator of VKC, and tear eosinophil count has been reported.
Mast cells: Through IgE-mediated degranulation, produce a biphasic response: immediate phase (histamine release) and late phase (leukotriene production).
Histopathology of conjunctival giant papillae shows eosinophil infiltration, fibroblast proliferation, extracellular matrix deposition, and numerous T cell infiltrates. That is, the formation of giant papillae involves not only type I allergic reactions but also T cell-dependent chronic inflammation.
According to the Japanese GL 3rd edition, the causative antigens of VKC are often house dust and mites, and it is not uncommon for patients to react to many other types of antigens such as pollen and animal dander7). Therefore, symptoms may persist year-round rather than only seasonally.
Age and sex: More common in boys aged 5–25 years. Frequently occurs during school age.
Climate: High prevalence in hot, dry regions (West Africa, Mediterranean coast, Middle East, India, East Asia). Association with summer temperature rise and urban heat island effect is also discussed.
Atopic predisposition: Frequent comorbidity or family history of atopic dermatitis, bronchial asthma, and allergic rhinitis.
Endocrine factors: Since the prevalence decreases after puberty, the involvement of sex hormones is suspected. An increased prevalence of growth hormone deficiency (GHD) has been reported in VKC patients 5).
VKC and atopic keratoconjunctivitis are allergic corneal diseases and also risk factors for infectious keratitis 6).
QWhy is it more common in boys?
A
The exact mechanism is not known, but there is a hypothesis that sex hormones promote eosinophil recruitment in the conjunctiva. Since the gender difference narrows after puberty and symptoms also decrease, endocrine factors are suggested to be involved. Additionally, boys tend to engage in outdoor activities more frequently than girls, leading to greater antigen exposure, which is also considered a contributing factor.
The 3rd edition of the guidelines uses three elements: clinical symptoms (A), type I allergic predisposition (B: systemic and local), and type I allergic reaction in the conjunctiva (C), to diagnose in the following three stages 7).
Diagnostic Category
Requirements
Clinical Diagnosis
A only (presence of clinical symptoms characteristic of ACD)
Clinical Confirmed Diagnosis
A + B (clinical symptoms + positive total IgE in tears, positive serum antigen-specific IgE, or positive skin reaction)
Definitive diagnosis
A + B + C or A + C (in addition to the above, eosinophils positive in conjunctival scraping)
As important diagnostic criteria for VKC, Table 2-5 of GL 3rd edition lists giant papillae, limbal proliferation, corneal lesions (shield ulcer, corneal plaque), eye pain, eye discharge, and hyperemia7). Clinical diagnosis is made based on characteristic clinical findings (cobblestone-like giant papillae, Horner-Trantas spots, shield ulcer) and history of itching and eye pain, and confirmed by laboratory findings.
The following examinations based on the Allergic Conjunctival Disease Clinical Practice Guidelines 3rd edition (GL 3rd edition) are combined according to disease type and severity7).
Eosinophil test in conjunctival scraping: After topical anesthesia, evert the upper eyelid, gently massage the palpebral conjunctiva with a glass rod, collect mucus from the conjunctival surface with forceps or a spatula, and smear it on a glass slide. After Hansel staining (Eosinostain®-Torii, Torii Pharmaceutical), it is judged positive if even one eosinophil is observed under a light microscope. The positive rate is high in VKC.
Tear total IgE test (Allerwatch® tear IgE, Wakamoto Pharmaceutical/Minalis Medical): A rapid diagnostic kit using immunochromatography, where a test strip is inserted into the lower conjunctival sac to collect tears. Results are available in about 10 minutes. Sensitivity for ACD is reported as 73.6%, specificity 100%, and caution is needed for false negatives7). The positive rate by disease type is highest in VKC at 94.7%, followed by AKC 80.5%, GPC 75.0%, PAC 65.4%, and SAC 61.9%7).
Serum antigen-specific IgE antibody test: Select antigens with high positive rates in patients with allergic conjunctival diseases, such as mites, house dust, Japanese cedar, orchard grass, and timothy grass (up to 13 items covered by insurance). Multi-item simultaneous measurement methods such as View Allergy 39 (Thermo Fisher Diagnostics) and MAST Immunosystems V (Minalis Medical) are available as screening tests under insurance coverage.
Skin test: Perform a prick test or scratch test, and judge as positive if the longest diameter of the wheal is 3 mm or more, or if the reaction is at least half of the positive control wheal. Perform with caution in patients with severe bronchial asthma, history of anaphylaxis, or significant cardiovascular disease.
Conjunctival provocation test: Not covered by insurance, and standard solutions are not commercially available, so it is rarely performed except for research purposes.
Eversion of the upper eyelid is essential: Giant papillae commonly occur on the upper palpebral conjunctiva, so observation by eyelid eversion is key to diagnosis.
Combined use of fluorescein staining: Active papillae are stained with fluorescein at the apex. Shield ulcers, superior corneal epithelial disorders, Horner-Trantas spots, and limbal lesions in mild cases are often first noticed by staining. Using a blue-free filter increases contrast and facilitates observation.
Papillae with a diameter of 1 mm or more are called giant papillae: This is a diagnostic criterion for vernal keratoconjunctivitis and giant papillary conjunctivitis.
Atopic keratoconjunctivitis (AKC): Onset in the 20s to 50s, predominantly in the lower palpebral conjunctiva, chronic course with conjunctival sac shortening and symblepharon. Complication of atopic dermatitis is essential.
Seasonal and perennial allergic conjunctivitis (SAC/PAC): No conjunctival proliferative changes. Papillae remain mild.
Giant papillary conjunctivitis (GPC): Caused by mechanical irritation from contact lenses, ocular prostheses, surgical sutures, etc. The major difference from VKC is rapid improvement upon removal of the cause.
Viral conjunctivitis: Unilateral onset, preauricular lymphadenopathy, and follicular formation. Caused by adenovirus, herpes simplex, varicella-zoster, enterovirus, etc.
Chlamydial conjunctivitis: Characterized by giant follicles in the lower fornix.
QHow accurately can VKC be diagnosed with the Allerwatch tear IgE test?
A
According to the Japanese guideline 3rd edition, the positive rate of Allerwatch tear IgE in vernal keratoconjunctivitis cases is 94.7%, the highest among allergic conjunctival diseases 7). For ACD overall, sensitivity is 73.6% and specificity is 100%. While specificity is high, sensitivity is limited, so it is important to interpret results in conjunction with clinical findings, keeping false negatives in mind. The test is a simple rapid diagnostic kit using immunochromatography, and results can be obtained in about 10 minutes by inserting a test strip into the lower palpebral conjunctival sac.
Treatment of VKC is based on the Japanese Guideline for Allergic Conjunctival Diseases 3rd Edition (2021) 7). Since Th2 cells play a central role in the pathogenesis of VKC, it cannot be controlled with anti-allergic eye drops alone, which lack T-cell suppressive activity. Combination with immunosuppressive eye drops or steroid eye drops that regulate T-cell function is necessary.
CQ Recommendations in the Japanese Guideline 3rd Edition
In the meta-analysis of CQ7, tacrolimus ophthalmic solution improved the corneal epithelial disorder score by a standardized mean difference of -0.89 (95% CI -1.32 to -0.46) and the palpebral papillae score by -0.83 (95% CI -1.68 to 0.03)7). Since no increase in intraocular pressure was observed, it is positioned as a first-line treatment for VKC7).
Mediator release inhibitors: Stabilize mast cell membranes and inhibit histamine release. Examples include sodium cromoglicate.
H1 receptor antagonists: Competitively inhibit histamine binding to receptors. Examples include olopatadine and epinastine. Selected when itching is severe. Administered prophylactically as preseasonal initial treatment.
Immunosuppressive eye drops
Cyclosporine ophthalmic solution (Papilock Mini® 0.1%): Launched in 2006. Instilled 3 times daily. Indicated for VKC under insurance. In a post-marketing all-case survey, significant improvement in both subjective and objective findings was observed from 1 month after starting instillation, and many cases reported reduction or discontinuation of steroid eye drops.
Tacrolimus ophthalmic solution (Talymus® 0.1%): Launched in 2008. Instilled twice daily. Indicated only for VKC (not indicated for AKC). Has stronger immunosuppressive effect than cyclosporine and is effective in steroid responders7).
Anti-allergic eye drops are the foundation, and immunosuppressive eye drops or steroid eye drops are added depending on severity and corneal lesions 7).
Baseline eye drops: 1) Patanol® 4 times daily or 2) Alegion® 4 times daily
During exacerbation: Add 3) Talymus® (tacrolimus) 2 times daily or 5) Flumetholon® 4 times daily
If no improvement: Change 5) Flumetholon® to 3) Talymus®, or add 4) Papilock Mini® (cyclosporine) 3 times daily
If no improvement with 3 drugs: Change 4) to 3) Talymus®
If still no improvement: Change 5) Flumetholon® to 6) Rinderon®
If uncontrollable with above: Consider oral steroids or surgical giant papillary resection
After improvement, first taper and discontinue steroid eye drops, then taper immunosuppressive eye drops. In case of relapse, restart immunosuppressive eye drops, and if still not controlled, add steroid eye drops.
VKC is common in young people, and it is important to note that younger individuals have a higher rate of steroid responders (steroid-induced glaucoma). Regular visits and intraocular pressure measurements are essential. High-potency steroids (Rinderon®) provide rapid effects but carry the risk of a vicious cycle of self-discontinuation upon improvement and subsequent worsening. Especially after age 10, when medication management shifts from guardians to patients, attention should be paid to decreased self-management ability.
If steroids are continued indiscriminately during remission, unlike the active phase where MBP and ECP maintain antibacterial effects, the risk of bacterial keratitis increases. In cases with atopic dermatitis, attention should also be paid to MRSA carriage/infection and induction of herpes simplex.
Shield ulcer/corneal plaque: Scrape the ulcer base or plaque with a golf knife or spatula. In principle, this should be performed after VKC has remitted. Performing it during the active phase may prolong epithelial defects and increase the risk of infection.
Excimer laser phototherapeutic keratectomy (PTK): Selected when corneal opacity remains after plaque removal. It can often remove the opacity without leaving residual haze.
Amniotic membrane transplantation: Performed to cover persistent epithelial defects. Amniotic membrane has anti-inflammatory and wound-healing promoting effects and is effective as a covering material for shield ulcers and persistent corneal epithelial defects. After surgery, continued control of the underlying disease with immunosuppressive eye drops is necessary.
If control is not achieved with immunosuppressive eye drops and steroid eye drops, consider the following:
Oral steroids: Oral steroids in children pose a risk of growth impairment, so the prescription should be as short as possible. If long-term administration is necessary, collaboration with a pediatrician is essential.
Local steroid injection (subtenon injection): Pay particular attention to elevated intraocular pressure.
Surgical giant papillary resection: Performed to remove inflammatory masses; complete resection is not necessary. It provides rapid effects, but continued use of immunosuppressive and steroid eye drops after surgery is essential. With advances in immunosuppressive eye drops, the need for surgical treatment has significantly decreased.
The GL 3rd edition recommends the following for prevention and self-care 7):
Removal of indoor dust mites: Keep the room clean at all times, and manage room temperature and humidity. Wash bedding at least once a week and vacuum frequently.
Pollen countermeasures: Wear goggles or sunglasses when going out, and wash your face after returning home.
Cold compresses: Cool the eyelid skin with a cold pack.
Artificial tears: To dilute antigens.
Guidance to avoid rubbing eyes: Avoiding mechanical stimulation also helps reduce the risk of developing keratoconus.
Initial treatment: If the season when symptoms worsen is known, starting anti-allergic eye drops before the season is effective.
QHow to choose between cyclosporine and tacrolimus?
A
Tacrolimus (Talymus®) has a stronger immunosuppressive effect than cyclosporine (Papilock Mini®). The Japanese guideline (3rd edition) strongly recommends the use of tacrolimus eye drops (evidence level A) 7). Tacrolimus is selected for severe cases, cases unresponsive to cyclosporine, and steroid responders. Cyclosporine is more effective for the bulbar type of VKC, while tacrolimus is more effective for cases complicated by atopic dermatitis. Anti-allergic eye drops, cyclosporine, tacrolimus, and steroid eye drops are selected stepwise according to severity 7). Proactive therapy with tacrolimus (continued at low frequency after remission) is effective in preventing recurrence.
The pathophysiology of VKC involves a complex immune reaction combining both type I allergy (immediate type) and type IV hypersensitivity (delayed type).
In type I allergy, antigens that enter the tear fluid trigger mast cell degranulation via IgE. In the immediate phase, histamine is released causing hyperemia and itching; in the late phase, newly synthesized mediators such as leukotrienes amplify inflammation.
In type IV hypersensitivity, Th2 cells produce IL-4, IL-5, and IL-13, promoting eosinophil recruitment and activation. Activated eosinophils release cytotoxic proteins such as MBP and ECP, causing direct damage to the corneal epithelium. Animal experiments have shown that type I allergy alone cannot induce conjunctival eosinophil infiltration, but the involvement of Th2 cells induces strong conjunctival eosinophil infiltration. This finding supports the central role of Th2 cells in VKC.
In recent years, the JAK/STAT pathway has been noted to play an important role in Th2 cytokine signaling. JAK1 mediates signaling of IL-4, IL-5, IL-13, IL-31, and TSLP (thymic stromal lymphopoietin), and is a central pathway in allergic inflammation 1). Therefore, JAK inhibitors are attracting attention as a new treatment option for refractory VKC.
Histopathology of conjunctival giant papillae shows eosinophil infiltration, fibroblast proliferation, extracellular matrix deposition, and numerous T cell infiltrates. The basic pathology of papillae is an angiogenic response, accompanied by conjunctival epithelial thickening and subepithelial inflammatory cell proliferation, with fibrous tissue protruding in a papillary shape. There is a central blood vessel surrounded by cell infiltrates mainly composed of lymphocytes and plasma cells. Giant papillae occur preferentially in the upper tarsal conjunctiva because they develop on the hard tarsal plate.
Histological examination of corneal buttons in the cicatricial stage of VKC revealed epithelial hyperplasia, loss of Bowman’s layer, stromal hyalinization, and neovascularization3). Immunohistochemistry showed loss of ABCG2 (a limbal stem cell marker) while the basal cell marker p63 was retained 3). This result suggests that limbal stem cell damage in VKC is not complete stem cell failure but rather partial functional impairment, which is an important finding for prognosis after corneal transplantation (DALK or PKP) 3).
In an 18-year-old female with severe VKC and atopic dermatitis, oral administration of upadacitinib, a selective JAK1 inhibitor, resulted in marked flattening of giant papillae within 2 months 1). Although this was a refractory case with a markedly high serum IgE level of 8973 IU/mL, a favorable course was achieved in combination with tacrolimus eye drops 1).
JAK1 mediates signaling of Th2 cytokines (IL-4, IL-5, IL-13, IL-31) and TSLP 1). JAK1 inhibition by upadacitinib comprehensively suppresses these cytokines and may represent a new treatment option for severe cases resistant to conventional immunosuppressive eye drops 1).
In a VKC family including monozygotic twins and their father, HLA analysis by next-generation sequencing (NGS) revealed associations of HLA-DQB105:01, HLA-DRB101:01:01, and HLA-A*32:01:01 with VKC 2). This is the first report of NGS-based HLA analysis in VKC 2).
In a study immunohistochemically examining corneal tissue in the cicatricial stage of VKC, epithelial hyperplasia, loss of Bowman’s layer, stromal hyalinization, and neovascularization were confirmed in 3 cases (4 eyes) that underwent DALK or penetrating keratoplasty3). Based on ABCG2-negative and p63-positive findings, partial limbal stem cell dysfunction was concluded 3).
Bilateral tarsal conjunctival keratinization was reported in a VKC patient with long-term disease (over 20 years since childhood onset) 4). This is the first case report of tarsal conjunctival keratinization in VKC 4). It was managed with lesion excision and conjunctival autograft, with no recurrence for 4 years 4). Corrected visual acuity of 0.8 (20/25) was achieved with scleral lens (PROSE) wear 4).
An increased prevalence of growth hormone deficiency (GHD) in VKC patients has been reported5). In an 11-year-old boy with VKC, GHD was confirmed, and marked improvement was observed 6 weeks after switching to tacrolimus eye drops and fluorometholone eye drops5). GH therapy has also been reported to reduce inflammatory markers such as CRP and IL-6, drawing attention to the involvement of GHD in the pathology of VKC5).
Effective cases of omalizumab, an anti-IgE monoclonal antibody, have been reported. Additionally, clinical trials of dupilumab, an anti-IL-4 receptor alpha antibody, are ongoing for atopic keratoconjunctivitis, and its application to VKC is also anticipated. These biologic agents may become new options for refractory cases that do not respond adequately to conventional immunosuppressive eye drops. However, while dupilumab is widely used for atopic dermatitis in dermatology, it is known to have a high incidence of ocular surface side effects such as conjunctivitis and blepharitis, so careful risk-benefit assessment is necessary when applying it to VKC.
The Japanese guideline 3rd edition7) lists future challenges including accumulation of evidence on long-term use of immunosuppressive eye drops, particularly long-term safety data of tacrolimus eye drops over 10 years, establishment of optimal combination protocols with steroid eye drops, follow-up of childhood-onset cases into adulthood, and RCTs on the timing of initial treatment. Furthermore, continuous nationwide epidemiological surveys to track temporal changes in VKC prevalence since the domestic prevalence survey are also important. Due to global warming and increased Japanese cedar pollen dispersal, the prevalence and severity of VKC may change in the future, necessitating continuous updates of epidemiological data.
QWill JAK inhibitors be used for VKC treatment in the future?
A
There is a case report that upadacitinib (a JAK1-selective inhibitor) was effective for refractory VKC1). Since JAK1 comprehensively mediates Th2 cytokine signaling, it theoretically has a mechanism of action consistent with the pathology of VKC. However, at present, it has not been approved for VKC and remains at the case report stage. Future clinical trials to verify safety and efficacy are expected. In the current GL 3rd edition, tacrolimus eye drops (Talymus®) remain the first-line treatment7).
Mima R, et al. Refractory vernal keratoconjunctivitis with atopic dermatitis improved by upadacitinib: a case report. Am J Ophthalmol Case Rep. 2024;35:102069.
Artesani MC, et al. Next-generation sequencing HLA typing with monozygotic twins and their father with vernal keratoconjunctivitis. Pediatr Allergy Immunol. 2021;32(7):1549-1553.
Jaffet J, et al. Histopathological and immunohistochemical analysis of corneal buttons in vernal keratoconjunctivitis. Ocul Surf. 2022;24:24-32.
Kate A, et al. Tarsal conjunctival keratinization in long-standing vernal keratoconjunctivitis: a case report. BMC Ophthalmol. 2022;22:182.
Fukushima A, Tabuchi H. A case of vernal keratoconjunctivitis with growth hormone deficiency. Cureus. 2022;14(10):e30615.
American Academy of Ophthalmology Cornea/External Disease Preferred Practice Pattern Panel. Bacterial Keratitis Preferred Practice Pattern. Ophthalmology. 2024;131(2):P1-P47.
