Introduction

The term “allergic conjunctivitis” (AC) describes an inflammatory reaction of the conjunctival layer caused by contact with an environmental allergen. Typical presentations of this condition include a strong desire to rub the eyes, redness (hyperemia), increased tear flow, and swelling and/or irritation of the eyelids [1, 2]. Typical environmental allergens include seasonal aeroallergens (e.g., pollen) and perennial allergens (e.g., dust mites, animal dander). Individuals experiencing AC frequently suffer from concurrent allergic rhinitis (AR) when they have allergic rhinoconjunctivitis (ARC) [2, 3]. Ocular allergy exists within a spectrum, ranging from mild to potentially vision-threatening conditions such as vernal keratoconjunctivitis (VKC), which has the potential for chronic inflammation extending beyond the conjunctiva to involve the cornea [3].

In terms of public health significance, AC is important due to its high prevalence, frequent recurrences, and functional disruption of activities, particularly in children and adolescents [3, 4]. Epidemiological assessments of AC indicate that regional variability exists and is influenced by the presence of concomitant allergic diseases (e.g., AR) and environmental factors such as climate and air pollution [3]. Studies demonstrate that ocular symptoms negatively impact health-related quality of life and can impair productivity in both work and school settings, thereby suggesting that AC is not merely a cosmetic or trivial annoyance [4, 5]. Epidemiologic estimates suggest AC affects a substantial fraction of the global population, with wide regional variability influenced by climate, allergen burden, air pollution, and comorbid atopic disease [3]. Additional practical burdens of AC, including concerns regarding the recurrence of AC symptoms and perceptions that management of AC is cumbersome, support the necessity for developing long-term approaches for managing AC beyond the episodic suppression of AC symptoms [6].

Current management of AC is typically multi-layered and consists of environmental avoidance of the allergen(s) responsible for the AC, supportive measures (e.g., cool compresses, artificial tears), and pharmacotherapy using topical antihistamines, mast cell stabilizers, dual-action agents, and topical corticosteroids or other adjunctive treatments as required [1, 7]. Recent clinical consensus guidelines (ICON) and reviews of AC indicate that dual-action antihistamine/mast cell stabilizer formulations are effective in reducing itch and are a common first line of therapy for AC. Topical corticosteroids are usually reserved for more severe cases due to adverse effects associated with prolonged use [1, 7]. Despite numerous available therapeutic options for managing AC, real-world control is often imperfect because AC is a highly heterogeneous condition and is often coexistent with dry eye disease. Recurrent AC with continued exposure to the offending allergen(s) results in diagnostic and treatment complexities in daily ophthalmology and optometry practice [3, 4, 8].

Mechanistically, AC should be viewed as a phase-linked inflammatory cascade rather than a single mediator problem. During the early phase of AC, mast cell activation and histamine release mediated by IgE are predominant and drive the rapid onset of itch and redness. The late phase of AC is characterized by lipid mediators and cytokines, leading to the recruitment and activation of various inflammatory cells that can prolong symptoms beyond the time frame in which histamine blockade alone is sufficient [7, 9]. Importantly for the focus of this review, research into allergies has increasingly emphasized that epithelial-derived “alarmins”, thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, and IL-25 serve as upstream signals to initiate type-2 immunity and amplify downstream effector circuits, including group 2 innate lymphoid cell (ILC2) responses [10–12]. Understanding these pathway components is important as they may reveal the cause of ineffectiveness of the current therapy [7, 9]. Antihistamines primarily address histamine-mediated symptoms; however, late-phase inflammation can persist through non-histaminic mediators (lipid mediators, cytokines/chemokines) and tissue recruitment programs described in consensus guidelines and immune response as key contributors to persistent disease activity [7, 9]. The disconnect between early symptom control and inadequate suppression of upstream/type-2 amplification and late-phase recruitment provides a clear justification for mechanism-based approaches to act earlier in the cascade or at convergence points [10, 11].

The purpose of this review is to (i) distinguish between mechanisms that have been shown to be supported by evidence derived from human clinical and/or tear biomarkers vs. those that are based on evidence obtained from animal and/or experimental models, (ii) create maps of pathways to therapeutic failure modes as they relate to each stage of disease (for example, the fact that patients experience continued symptoms after H1 histamine blocking), and (iii) integrate the data regarding epithelial alarmins, mast cell mediators of non-histamine activity, recruitment biology, and neuroimmune signaling related to itch with an understanding of how these may provide upstream and convergent targets to achieve steroid sparing [7, 13, 14]. By relating epithelial alarmins, type-2 cytokine networks, and phase-specific effector biology to treatment performance and limitations, we intend to identify areas where current approaches fail mechanistically and provide the most plausible “next-step” targets for safer, longer-lasting disease control.

Conjunctiva, disease phenotype, and immune response

The surface of the eye is far more than a simple protective window. It functions as a highly active immunological barrier. The focus of this complex system is the conjunctiva, a thin, transparent mucous membrane that lines the inner eyelids and covers the white part of the globe. The conjunctiva protects and lubricates the eye, lining the inside of eyelids (palpebral conjunctiva) and covering the white part of the eyeball (sclera, called the bulbar conjunctiva), connecting them at the fornix and preventing irritants from entering. Structurally, it consists of a stratified epithelial layer resting upon a vascularized connective tissue known as the substantia propria. This tissue houses the conjunctiva-associated lymphoid tissue (CALT), which acts as a local immune security force for the eye, containing a high density of mast cells, lymphocytes, and dendritic cells [1]. While the epithelium and its goblet cells produce a protective mucus layer to trap debris, this expansive surface area also serves as a primary landing space for environmental aeroallergens, including but not limited to pollen and animal dander.

The most common and typically milder forms of AC are seasonal AC (SAC) and perennial AC (PAC) (Figure 1). The SAC and PAC mechanism of immune response begins with a sensitization phase to an initial, novel exposure of the conjunctival mucosa to environmental allergens [7, 15]. For SAC, these include tree and grass pollen during the spring and summer months, while PAC is induced by house mites, dust, pet dander, and mold, throughout the year (Figure 1). These allergens activate innate immune cells, such as neutrophils and macrophages, using toll-like receptors (TLRs) [7]. Once TLRs are activated, they trigger antigen processing and presentation, for which antigen-presenting cells (APCs) activate naive T lymphocytes. The T cells can then interact with B lymphocytes exposed to similar allergens, releasing IL-4 to direct B cells to class switch to synthesize allergen-specific IgE antibodies. These antibodies bind to high-affinity IgE receptors (FcεRI) on conjunctival mast cells and basophils. These cells become sensitized and primed for future allergen exposures [7, 15].

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Figure 1. Risk factors, types, and types of conjunctivitis and allergic conjunctivitis. Created in BioRender. Rai, V. (2026) https://BioRender.com/gofy7z2.

The pathophysiology of AC provides a classic example of a Type I hypersensitivity reaction [16], which typically occurs in two waves. When an allergen contacts the eye of a sensitized individual, it cross-links IgE antibodies bound to FcεRI that are already “primed” on the surface of conjunctival mast cells [15, 17]. This event triggers mast cell activation and subsequent degranulation. Mast cell degranulation releases pre-formed inflammatory mediators, most importantly histamine, driving the early phase of SAC. Histamine acts through H1 receptors in the conjunctiva and, upon activation, increases intracellular inositol phosphate and calcium to induce itching, vasodilation leading to redness, and increased microvascular permeability leading to tearing and edema [1, 7, 14, 15]. This early response happens within minutes, creating the immediate discomfort that patients frequently report.

The reaction does not conclude once the initial surge of histamine fades. The late-phase response, which typically occurs 6–12 hours after allergen exposure. Following mast cell activation, a second wave of inflammation develops due to the de novo synthesis of inflammatory mediators such as prostaglandins and leukotrienes in tear fluid [1, 7, 14, 17] (Figure 1). Prostaglandins increase microvascular permeability, leading to worsening conjunctival hyperemia, increasing histamine-induced itching, and stimulating goblet cells, which increase mucus secretion. Leukotrienes work in tandem with histamine and prostaglandins to increase vascular permeability and promote oedema formation. The late phase is sustained by way of cellular infiltration into the conjunctiva [1, 7, 14]. Tumor necrosis factor α (TNF-α) up-regulates adhesion molecules such as intracellular adhesion molecule 1 (ICAM1), which facilitates leukocyte adhesion and migration into conjunctival tissue [7]. Furthermore, Th2 lymphocytes mature during this phase, which release IL-4, IL-5, and IL-13 cytokines. IL-4 and IL-13 specifically form giant papillae through conjunctival fibroblast stimulation and IgE overexpression. IL-5 acts on eosinophils to cause persistent inflammation and may increase long-term conjunctival damage [1] (Figure 1). These chemical messengers act as beacons, recruiting reinforcements from the bloodstream, specifically calling for eosinophils and Th2 cells [1, 2, 16, 17]. In chronic or severe clinical phenotypes, the persistent presence of these cells can lead to significant tissue remodeling and corneal complications. Recent research suggests that the conjunctival epithelium is not merely a passive barrier; it functions as a more active barrier. When stressed or damaged by allergens, it releases alarmins (such as TSLP, IL-33, and IL-25) that serve as master switches [16]. These proteins kickstart the innate immune pathways that sustain the inflammatory cycle and drive persistent disease.

Another form of AC includes VKC (Figure 1). Occurring primarily in male children during the first 10 years of life, VKC is a chronic conjunctival and corneal inflammation due to exposure to airborne environmental allergens [18]. While symptoms can occur perennially, they typically onset in spring and exacerbate in the summer. VKC is a severe ocular allergic disease of childhood characterized by chronic or recurrent conjunctival and corneal inflammation with prominent type-2 skewing and eosinophil-rich infiltration [18–20]. Sensitization and IgE involvement are variable across patients; while many exhibit systemic atopy and evidence of allergen sensitization, disease activity can persist beyond classic episodic IgE-driven mechanisms [18, 20]. As allergen exposure induces IgE production, it binds to FcεRI receptors on mast cells, basophils, and dendritic cells. This results in IgE cross-linking, which triggers mast cell degranulation to mediate the release of histamine, tryptase, and TNF-α to further amplify inflammation [19, 20]. Overall, VKC is driven by a strong type-2 inflammatory program in which IgE-dependent pathways may contribute but are not uniformly dominant across all patients. This establishes VKC as a chronic allergic disease influencing IL-4, IL-5, and IL-13 cytokines, and eosinophilic recruitment similar to SAC and PAC. Specifically for VKC in relation to eosinophils, they also release cytotoxic granule proteins such as eosinophil cationic protein (ECP) and major basic protein, which damage corneal epithelial cells, cause punctate keratitis, and drive the formation of vernal shield ulcers [18, 21]. Lastly, VKC tends to show increased involvement of pattern recognition receptors in conjunctival tissues to sustain inflammation even when allergen exposure fluctuates [18].

Allergic keratoconjunctivitis (AKC) (Figure 1) is a severe form of AC. It is a chronic, noninfectious conjunctival and corneal inflammatory disease clinically and immunologically distinct from SAC and PAC. Most notable is its atopic model involving body systems outside of the eye. It is more than merely an IgE-mediated response and is driven mostly by T-cell responses [22, 23]. The defining features include persistent inflammation, progressive tissue injury, fibrosis, and poor response to antihistamine therapy [22]. Although similar to the previously stated ocular allergies, such as the IgE pathway, eosinophils, and mast cells, individuals with AKC typically exhibit reduced innate immune responses. These include a reduction in keratinocyte antimicrobial peptides and reduced tear deficiency, which can induce recurrent ocular infections to increase inflammation and injury [24]. Centrally, AKC is induced by T-cell immune responses where Th1 delayed hypersensitivity leads to elevated interferon-γ (IFN-γ), increased IL-2, and IL-12. As a result, conjunctival scarring, fibrosis, and notably the poor anti-allergic therapy response make AKC most notable [24, 25].

One unique case of AC includes giant papillary conjunctivitis (GPC) (Figure 1). The disease is an ocular surface inflammation disorder typically associated with contact lens wear, such as soft contacts and extended-wear lenses [26]. GPC has also been noted in ocular protheses, exposed sutures, corneal grafts, and post-surgical foreign material. It is centrally induced by mechanical irritation. This allows contact lens surfaces to quickly accumulate mucus, proteins, bacteria, and airborne particles, increasing conjunctival hyperemia and injection. The immune response is mediated by IgM antibodies in tears, which indicate a local immune reaction rather than a systemic reaction [27]. Mast cell degranulation occurs secondary to mechanical stimulation, which does not induce IgE cross-linking. ECP levels and Th2 responses are also elevated but lower than VKC [27].

Inflammatory response of the eye

AC is increasingly viewed as a mucosal inflammatory disorder of the ocular surface, rather than just a “transient irritant” conjunctivitis. This is because the conjunctiva is located at an extremely high exposure site and has developed its own immune structure, which allows it to respond to antigens in a highly organized manner [1, 28]. Human studies have shown that CALT exists as organized lymphoid tissues containing intraepithelial lymphocytes, subepithelial follicles, and surrounding lymphatic and blood vessels. These findings suggest that ocular surface immunity is built into the eye [28, 29]. The presence of CALT and drainage-associated lymphoid tissue in histological and ultrastructural studies of the human conjunctiva further supports that the conjunctiva can sample antigens and regulate local immune responses [30, 31]. Modern frameworks of mucosal immunology position the ocular surface as part of a larger mucosal immune network. This helps explain why there is a commonality among ocular allergies and other upper airway allergic diseases [28, 32].

During AC, the inflammatory response is generally mediated by IgE-dependent mast cell activation, leading to an influx of inflammatory cells, a model which has been repeatedly reviewed and discussed in both clinical and translational research [1, 13, 32] (Figure 2). In sensitized individuals, the cross-linking of IgE on mast cells results in the rapid degranulation and release of various mediators, resulting in symptoms such as itching, redness, tearing, swelling of the eyes, and chemosis [1, 13]. One major point of convergence in the literature is that the early phase of AC does not occur in isolation from the later phases of inflammation. Early mediator release promotes the subsequent generation of lipid mediators (such as prostaglandins and leukotrienes), chemokines, cytokines, adhesion molecules, and chronic mast cell activation that contribute to the chronic inflammation found in more sustained forms of AC [13]. This connection is important clinically since therapies that primarily reduce early-phase mediator levels may not completely suppress the ongoing cellular response found in chronic forms of AC [13, 32] (Figure 2).

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Figure 2. Molecular mechanisms of inflammation of the conjunctiva in allergic conjunctivitis. Allergic conjunctivitis is an immune response, primarily IgE-mediated, involving two phases: an immediate release of histamine from mast cells after allergen exposure, causing itching/redness; and a later phase with inflammatory cells (eosinophils, T-cells) infiltrating, driven by cytokines (IL-4, IL-5, IL-13) from Th2 cells, leading to persistent inflammation, mucus, and tissue changes. This cascade involves allergen cross-linking IgE on mast cells, degranulation, and signaling pathways that recruit more immune cells, causing symptoms like tearing, redness, and swelling (chemosis). IL: interleukin; DC: dendritic cells; APC: antigen-presenting cell; VKC: vernal keratoconjunctivitis; AKC: allergic keratoconjunctivitis. Created in BioRender. Rai, V. (2026) https://BioRender.com/fs6ssw1.

The late phase of AC typically occurs due to recruitment and retention of inflammatory cells in the eye. This is achieved through the action of chemokines and their associated adhesion pathways, converting the initial mediator burst into an inflammatory cell occupation of the eye [13, 33]. Chemokines are specifically identified as critical for organizing the late phase of allergic responses. They recruit and activate leukocytes (including neutrophils, eosinophils, and Th2 lymphocytes) to the conjunctival mucosa [13, 33] (Figure 2). Eotaxin [C-C motif chemokine ligand 11 (CCL11)], IL-8, monocyte chemoattractant protein (MCP-1, MCP-2, MCP-3, MCP-4), Regulated upon Activation, Normal T cell Expressed and Secreted (RANTES, also known as CCL5), macrophage inflammatory protein-1 alpha (MIP-1α/CCL3), and CCL17 are common chemokines involved in the later phase of AC. Activation of leukocytes contributes to the sustained inflammation and symptoms characteristic of the late-phase reaction and thus represents an important mechanism for prolonging symptomatology beyond histamine [17, 34, 35]. The detection of eotaxin and IgE in the tears of human patients suffering from SAC suggests a relationship between chemokines and the pathophysiology of ocular allergic disease. The study proposed that these two biomarkers represent separate aspects of the allergic process, and not redundant signals [35]. Up-regulation of eotaxin-1 in tears during seasonal disease periods, as observed in previous studies, suggests a common link between tear chemokines and symptomatic ocular allergy [36] (Figure 2). Expression of chemokines in more severe ocular allergic disease (VKC) demonstrates elevated expression of RANTES (CCL5), eotaxin, and MCPs in the conjunctiva of VKC patients. This provides further evidence that environments rich in chemokines are associated with chronic inflammation and ocular surface damage [37].

While chemokines provide a gradient for the migration of leukocytes into the inflamed tissue, the literature clearly demonstrates that the adhesion molecules [like ICAM-1, VCAM-1 (vascular cell adhesion molecule 1), E-selectin, and VAP-1 (vascular adhesion protein-1)] expressed on the surface of vascular endothelium and other cells within the eye act as “entry permits” for leukocytes to migrate into the inflamed eye alongside anti-adhesive molecules like endomucin that maintain vascular quiescence [37, 38] (Figure 2). For example, examination of the level of ICAM-1 on the conjunctival epithelial layer and the levels of ECP in the tears of children suffering from AC demonstrated significantly higher levels of ICAM-1 and ECP than in healthy controls. This study demonstrated a direct association between epithelial adhesion biology and eosinophil activation in the ocular surface microenvironment [38]. Experimental studies examining the role of adhesion molecules in murine models of AC have also provided strong evidence for a causal role for the interaction of very late antigen-4 (VLA-4) and VCAM-1 in eosinophil recruitment into the conjunctiva after allergen challenge. Specifically, studies using either antibodies against VLA-4 or VCAM-1 have shown that blocking these molecules can inhibit eosinophil recruitment into the conjunctiva after allergen challenge [39]. More broadly, classical immunology studies have shown that IL-4 can induce VCAM-1 expression on the surface of endothelial cells and promote adhesion of eosinophils and basophils through the interaction of VLA-4. This represents an important cytokine-to-adhesion pathway that links type 2 cytokine signaling to leukocyte recruitment and activation. This is consistent with the established understanding of type 2 cytokine signaling in allergic disease [40].

A key refinement to current mechanistic discussion of ocular allergy is that “histamine biology” alone cannot account for ocular allergy in chronic itch [13, 41]. Histamine-independent mechanisms are associated with allergic ocular itching, including evidence from animal models that TRPA1 neuronal signaling is necessary to develop allergic ocular itching. This indicates that non-histaminergic neural mechanisms may generate symptoms in some subsets of disease [41]. The neuro-immune model is consistent with the translational clinical observation that simply managing the early mediator phase will not necessarily resolve later inflammatory events that maintain late phase symptoms [13, 32].

The “innate immune pathway” model is being increasingly used to characterize the initial signals that predispose ocular surface inflammation to type-2 responses before the typical Th2 effector cascade responses [42, 43]. A recent review of cytokines related to AC summarizes the role of IL-4, IL-5, IL-13, and epithelial-derived cytokines such as IL-33 and TSLP, often viewed as the initial triggers of allergic inflammation [42]. There is also evidence from experimental studies supporting the pollen/TLR4 to IL-33/ST2 pathway in AC models caused by short ragweed pollen, demonstrating an association between an innate receptor pathway and increased type-2 cytokine production due to IL-33/ST2 signaling [43]. Observations in humans also support the importance of epithelial “alarmin” biology by demonstrating the presence of TSLP on the ocular surface and downstream type-2 cytokines (IL-4, IL-5, IL-13) in conjunctival scrapings and tears of patients representing all types of AC [44].

Molecular mechanisms of inflammatory response

Management and current treatment

Existing therapies for managing AC follow a stepwise approach depending on the severity of the condition and the risk to the ocular surface. The primary goal of current treatment is to reduce the early phase mast cell-mediated response to relieve symptoms and to manage the late phase cellular inflammation caused by eosinophils, Th2 lymphocytes, cytokines, and chemokines in more severe cases [1, 32].

Challenges and future directions

There is an overwhelming consensus among mechanistic reviews over the last few years to push “next generation” therapies for AC upstream and away from just controlling histamine to disrupting the early cascade, blocking the type-2 immune response, and suppressing the late phase recruitment of cells into the eye. This is because the persistence of AC is due to the cytokine and chemokine networks and trafficking of cells, and not a single mediator [13, 33, 42]. Cytokines (such as IL-4, IL-5, IL-13, and epithelial alarmins, including IL-33/IL-25/TSLP) involved in the type-2 immune response have repeatedly been referred to as mechanistic “control knobs” that determine the level of disease and chronicity of AC. Therefore, these control knobs would be logical targets for steroid-sparing treatment strategies [16, 42]. Chemokines have also been identified as playing a major role in the formation of the late-phase inflammatory infiltrate, particularly in terms of eosinophils, and therefore represent a potential target for therapeutic intervention, specifically to address the clinical problems of prolonged symptoms and tissue damage seen in the more severe forms of AC [16, 33].

An additional upstream strategy includes inhibiting the reactive aldehyde species that enhance the inflammatory signaling process. In the phase 3 INVIGORATE allergen chamber study, the reactive aldehyde species modulator reproxalap was found to meet both primary and key secondary endpoints of reducing ocular itching and redness compared to vehicle, providing support for the idea that early chemical mediators can be therapeutically targeted in AC. A second phase 3 program (ALLEDIVIATE) has been registered for AC as well, indicating continued late-stage interest in this upstream mechanism as a steroid-free option. The practical “proposition” suggested by these data is that aldehyde modulating therapy may provide a bridge between antihistamines (rapid symptom relief) and immunosuppressants (widespread control), to reduce the late phase recruitment of cells that is dependent on prior amplification, while avoiding the side effects of steroids [55].

Since many cytokines relevant to AC act through the JAK/STAT pathway, topical JAK inhibition represents a potentially useful strategy to inhibit multiple cytokine inputs (signaling associated with IL-4, IL-5, IL-13) with a single class of small molecules [42, 63]. While direct AC evidence primarily exists as preclinical/experimental data, as opposed to late-stage clinical data specific to AC, tofacitinib has been demonstrated to suppress mast cell degranulation and decrease allergic inflammation in experimental AC models [56]. Ophthalmic exposure data that will inform the feasibility of delivering tofacitinib topically come from studies of topical ophthalmic tofacitinib in other ocular surface inflammatory diseases (i.e., dry eye disease), which demonstrated immunomodulatory effects. Thus, while AC-specific trials are limited, these studies demonstrate the plausibility of using topical ocular delivery for AC [63]. Therefore, a reasonable near-term direction is translation/re-purposing of other drugs or small molecules. Prioritizing well-designed AC studies (both allergen challenge and field trials) to assess whether topical JAK inhibition can decrease the late phase signs and persistent itch beyond what dual-acting antihistamines can achieve is needed [13, 42].

Prostaglandin signaling, particularly PGD2 acting via DP2/CRTH2, has been experimentally demonstrated as an AC-relevant effector pathway and is continually referenced in therapeutic target overviews as a logical target [46, 50]. In a mouse model, decreased ocular inflammation post-allergen exposure with topical DP2 antagonism as a new therapeutic option for AC, specifically associating CRTH2 blockade with the late phase, not with the immediate histamine blockage of the early phase [50]. Systemic CRTH2 antagonism has also shown clinical relevance to AC by decreasing ocular and nasal symptoms in allergic individuals challenged with allergens; thus, demonstrating that the pathway is involved in generating ocular symptoms [64]. The potential future implication is that CRTH2-directed agents (preferably topical) could be assessed as add-on or alternative therapies for patients who have persistent itch/redness despite optimization of their antihistamine regimen [13, 50].

Chemokines are repeatedly referred to as the “cell traffic controllers” of late-phase AC. The effects of chemokine concentration gradients in recruiting eosinophils and Th2 lymphocytes and the presence of chemokines in tears, as discussed above, provide a link between chemokine activity, disease phenotype, and a rationale for chemokine inhibition in both a mechanistic and clinical sense [16, 33, 34]. Involvement of chemokine receptors (e.g., CCR6) in allergic conjunctival inflammation in experimental models provides evidence for receptor-level targeted approaches compared to CCR3-centric eosinophil-based concepts alone [33, 65]. A practical proposal stemming from a two-step strategy: (1) identify a patient’s dominant recruitment signature via tear biomarkers (e.g., eosinophil-attracting chemokines) and (2) match this signature to a receptor/ligand antagonist-based approach to reduce late-phase signs generated by the infiltrates [33, 34].

If chemokines serve as the “GPS”, adhesion molecules are the “hardware” that leukocytes need to access tissue, thereby allowing recruitment blockade to serve as a complementary approach to chemokine antagonism [46, 62]. Mice lacking the ability to interfere with the VLA-4/VCAM-1 interaction had reduced eosinophil invasion into the conjunctiva and reduced experimental AC, establishing adhesion pathways as a causal mechanism as opposed to mere correlations [39]. Therapeutic-target syntheses explicitly include integrins and associated recruitment machinery (e.g., ICAM-1-linked interactions) as potential future areas of investigation for AC because they operate at a critical convergence point for multiple inflammatory triggers [46].

Blocking the cellular signal of mast cells using FAK inhibitors as a “mast-cell” suppressant. The “hub strategy” of convergence inhibits the cellular signaling involved in mast-cell effector functions instead of inhibiting individual mediators downstream of the mast-cell effector function. Pharmacological inhibition of FAK, suppressing the allergic inflammatory responses and clinical signs of allergic disease in an AC mouse model, suggests that FAK plays a role in FcεRI-linked mast-cell degranulation signaling. This directionally supports further testing of FAK inhibition (and related kinase nodes) as a method of reducing both mast-cell outputs that depend upon histamine and those that do not require histamine without utilizing corticosteroids [46, 57].

Topical steroids remain effective; however, their utility is limited due to systemic exposure associated with repeated use. Selective glucocorticoid receptor agonists (SEGRAs) continue to be considered as a viable option to provide the anti-inflammatory efficacy of steroids with a reduction in the systemic elevated pressures/cataracts, typically associated with long-term steroid use [58, 66]. Mapracorat (SEGRA) was found to induce apoptosis of eosinophils in the conjunctiva during late-phase ocular allergy models, and thus its effect was directly aligned to the later-phase infiltrate that causes chronicity [58]. There is an active clinical trial record (NCT01289431) for mapracorat ophthalmic formulation in AC, supporting that this is not simply speculative and has progressed to human trials.

The most significant challenge to treating AC is heterogeneity, seasonal vs. perennial disease, mild SAC/PAC vs. severe VKC/AKC. The increasing number of review articles is advocating for biomarker-based stratification to avoid a one-size-fits-all, all-escalating treatment approach [16, 17]. Tear biomarkers have been proposed and reviewed for allergic conjunctival diseases, including chemokines that correlate with severity and biomarkers that can potentially identify phenotypes or monitor response, providing a basis for a personalized medicine approach [34, 67]. Periostin continues to be referenced as a type-2 inflammation-linked biomarker in multiple allergic disease contexts, including ocular allergic disease contexts, providing support for its possible application in ocular phenotypes characterized by high levels of type-2 inflammation [68].

Topical treatments may fail even if the mechanisms are correct due to short residence times, poor penetration into the eye, preservative intolerances, and compliance issues; therefore, drug delivery is becoming a primary component of the therapeutic target [69, 70]. Ocular delivery via nanotechnology has been developed to enhance the retention and penetration of the active ingredient(s) in addition to providing long-lasting (sustained) release. This strategy is important for anti-inflammatory agents requiring chronic/long-duration exposure to downregulate late-phase biology [70, 71]. An example of advancements in delivery/formulations of topical treatments for ocular allergies is the development of preservative-free, once-daily topical antihistamines. Bilastine 0.6% preservative-free formulations were found to demonstrate rapid onset and prolonged duration in randomized clinical trials, thereby demonstrating how advances in formulation can provide improved real-world control for patients using existing drug classes [72, 73]. A forward-thinking approach is that “mechanism-forward” drugs (i.e., aldehyde modulators, kinase inhibitors, CRTH2 antagonists) will most likely require parallel advancements in delivery (preservative-free multidose, sustained-release delivery systems, contact lenses, and/or in-situ gelling platforms) to obtain consistent therapeutic exposure at the ocular surface [69, 70].

Ongoing clinical trials

Clinical trials are essential for developing new therapies by rigorously testing potential treatments (drugs, devices, vaccines) in humans, proving their safety, effectiveness (efficacy), and optimal dosage, transforming lab discoveries into approved, life-saving medicines, and providing evidence to regulatory bodies like the FDA for patient access, all through structured phases (I–IV) that assess risks vs. benefits for better care. Table 1 summarizes the ongoing clinical trials for AC.

Conclusions

The clinical challenge posed by AC is best understood from an immunological standpoint as an active inflammatory process due to a combination of innate and adaptive immune processes. Early symptoms are due to rapid mediator-related release from activated mast cells; however, persistent symptoms reflect late-phase responses supported by continued production of lipid mediators and cytokines/chemokines. Epithelial-derived signals such as TSLP, IL-33, and IL-25 can activate and sustain type-2 inflammatory responses via ILC2. Finally, neuroimmune signaling also explains why ocular itch can continue even when histamine release is blocked. The above mechanistic rationale supports the view that antihistamines alone are often insufficient for the treatment of many patients with AC and supports the use of next-generation therapies directed at interrupting the upstream amplification of the response. Further advances in this area are likely to occur when combining mechanism-based therapeutic targets with biomarker-based stratification of patients and improved ocular delivery systems to allow for more durable efficacy with reduced toxicity and increased compliance.