The eye is vulnerable to irritants as it is in constant contact with the environment. In turn, the ocular mucosa is immunologically active and can easily react to allergens. Ocular allergies, otherwise referred to as allergic conjunctivitis, affect approximately 40% of the population [1,2]. Although ocular allergies may present on their own, they are often associated with allergic rhinitis. Previous literature finds that 20% of allergic rhinitis patients present with allergic conjunctivitis, but more recent studies reflect that ocular symptoms may be as bothersome as nasal symptoms [3,4,5▪▪]. Furthermore, atopic patients may also suffer from allergic conjunctivitis in addition to other allergies. Patients with ocular allergies also experience a significant impact on quality of life as symptoms include watery, itchy, red, sore, swollen, and stinging eyes [3,4,5▪▪]. Unfortunately, many cases often times go undiagnosed or patients self-treat which leads to poor quality of life and substantial costs. In the United States alone, the annual cost of allergic rhinoconjunctivitis is approximately 2–4 billion dollars [6,7]. Successful management involves both proper diagnosis and treatment.
Over the years, different treatments have been developed for ocular allergies. Although many of the older formulas were approved for ocular treatment for their direct impact of ocular pruritus most have failed to gain approval for redness, but there are newer products currently on the market that continue to address these benchmarks. The following will explore current available treatments, including older medications, repurposed drugs, and more novel methods of administration.
The allergic eye
Ocular allergies encompass a number of conditions because of corneal inflammation. Of these, seasonal allergic conjunctivitis and perennial allergic conjunctivitis are the most common ocular allergy and affect 15–25% of the population. More severe conditions include atopic keratoconjunctivitis (AKC), vernal keratoconjunctivitis (VKC), and giant papillary conjunctivitis (GPC). The latter, GPC is actually a reaction to repeated irritation but has been categorized with other allergic conditions [4,8].
The immunopathophysiology is an important step to understand the proper sequence of appropriate treatment for ocular surface disorders. Ocular allergies are mediated by the immunoglobulin E-mast-cell system triggered by allergens eliciting histamine release and subsequent proinflammatory mediators such as prostaglandins, leukotrienes, and cytokines, ultimately recruiting eosinophils, neutrophils, and macrophages leading to a late-phase reaction of the conjunctival tissues. These events lead to the inflammatory reaction manifested by ocular injection (redness), swelling (chemosis), itching (pruritus), and tearing as well a possible white ropey discharge .
Ocular allergy treatment
Many patients tend to first manage their ocular allergies with self-treatment and over-the-counter medications. Although this does not have a significant consequence, it does lead to a continuous decrease in quality of life until proper treatment is initiated [3,4,5▪▪]. Recent studies show that patients use different combinations of decongestants and antihistamines, regardless of current recommendations and specific diagnosis. In general, the treatment is stepwise, beginning with nonpharmaceutical agents such as cold compresses and progressing to different topical and oral medications (Fig. 1) [1,3,4,5▪▪].
Of the pharmaceutical agents available, antihistamines, mast-cell stabilizers, and dual-action agents are the most common. Most recently in the United States, the 0.24% ophthalmic solution of cetirizine completed its phase 3 trial for treatment of allergic conjunctivitis and has been approved by the Food and Drug Agency .
Antihistamines target a key factor in allergic conjunctivitis and have therefore been widely available on the market for the treatment of allergic conjunctivitis.
When studying antihistamines, an appreciation of the impact of different histamine receptors (H1–H4) and their effects are required. H1 and H4 are largely responsible for pruritus, whereas H2 leads to vasodilation and thus to the redness patients suffer from in allergic conjunctivitis. H3 receptors have an immunomodulatory effect as their stimulation inhibits the release of histamine, however, currently there are no available drugs targeting H3 receptors [8,11].
Historically, systemic antihistamines were used for control of ocular allergies and were known to have different affinities to the various histamine receptors (Fig. 2). This translates into variable efficacy and duration of action. As such, there has been, and continues to be, development of efficacious antihistaminic treatments. Moreover, patients’ comfort with using topical antihistamines is also paramount as initial solutions would cause a burning sensation .
In general, second-generation antihistamines are preferred as they cause less sedative side-effects [2,5▪▪,12]. Beginning in the 1990s, the topical antihistamines such as levocabastine and emedastine were popular. Although traditional oral antihistamines do offer relief of ocular symptoms and require less frequent dosing, response is variable and may be accompanied by adverse effects such as pupillary changes, blurred vision, and the exacerbation or development of tear film dysfunction, for example, dry-eye syndrome. Furthermore, seeing as ocular allergies is often associated with rhinitis, oral antihistamines are usually complemented with intranasal steroids, or decongestants which act as vasoconstrictors. Many patients also require the concomitant use of lubricating eye drops and oral antihistamines to maximize control of ocular allergy symptoms .
Although the combination of both antihistamines and decongestants is synergistic and leads to either partial or complete relief of symptoms, it presents with the risk of rebound hyperemia and conjunctivitis medicamentosa.
Bilastine was approved in the last decade for use in allergic rhinoconjunctivitis. It is an H1 antagonist that does not possess CNS depressant effects. In studies, bilastine was shown to significantly improve ocular manifestations. Owing to its efficacy in treating conjunctival redness, itching, and tearing, it is now being reformulated into a topical ophthalmic solution . A recent multicenter, double-masked, randomized phase 3 study was completed in August 2018, comparing the efficacy of bilastine ophthalmic solution 0.6% to vehicle and ketotifen for the treatment of allergic conjunctivitis. However, results are still pending .
Although bilastine is still undergoing trials as an ophthalmic solution, cetirizine was recently approved in the United States for topical ophthalmic use. Cetirizine was used for many years in the oral form. It is a H1-histamine receptor blocker used to treat a number of allergic conditions including seasonal and perennial allergic rhinitis, and urticaria [10,12].
Owing to its antihistaminic potency and efficacy in providing significant therapeutic relief in treatment of symptoms associated with allergic conjunctivitis, cetirizine was also reformulated into an ophthalmic solution. It is both safe and convenient to use and has considerable clinical efficacy. Several studies have shown reproducible results with an onset of action at 15 min and an 8-h duration of action, whereas the oral formulation had 24 h duration of action. This duration translates into a decrease in need of repeated application of cetirizine, compared with other formulas which require administration twice to four times per day. The cetirizine ophthalmic solution is formulated with lubricants that appear to provide additional comfort upon administration. The primary endpoint, as with other ophthalmic antiallergic agents, is a dramatic decrease in ocular pruritus (‘itch’), and a decrease in conjunctival swelling (chemosis) similar to cetirizine's efficacy on urticaria. The completed phase three trial of cetirizine 0.24% solution resulted with significantly decreased ocular itch and redness. The mean difference in ocular itch was greater than 1 unit with a P-value less than 0.0001[10,14].
In addition to ophthalmic antihistamine solutions, contact lenses containing the antihistamines are also under investigation . Of these, ketotifen is a high-affinity antagonist of the H1 receptors and also possesses mast-cell stabilizing properties. Contact-lens users who suffer from ocular allergies tend to either not use their contacts during allergy season, or they rub their eyes which may cause damage to both their contact lenses and eyes. Contact lenses containing other drugs such as epinastine and olopatadine are being studied as well. These various studies exhibit clinically significant decrease ocular itch for up to 12 h posttreatment. The results are promising as the use of contact lenses allow for a two-in-one action, where there is both a physical barrier to allergens and prolonged release [13,15]. Of these studies, two multicenter trials conducted a conjunctival allergen challenge for ketotifen containing lenses that demonstrated a reproducible decrease in mean itch score of greater than 1 unit at all time points .
Mast-cell stabilizers such as cromolyn or nedocromil are not as effective in treating ocular allergies because of their requirement of initiation prior to the exposure to allergen for maximum effect as a prophylactic measure which also leads to decreased compliance than other conventional antiallergic ophthalmic agents . They are rarely used as monotherapy.
Topical dual-activity agents
Dual-agent drugs encompass both antihistaminic and inhibition of mast-cell degranulation properties, thus providing immediate relief via their antihistaminic effects, and prophylactic management through mast-cell stabilization. Many of these agents also have secondary effects such as inhibition eosinophil migration, cytokine activation, and other inflammatory mediators. They are commonly utilized as the first-line treatment. Olopatadine for many years was the ‘gold standard’ as it was the first dual-acting eye-drop treatment . Not only does it possess high affinity to the H1 receptor, it also inhibits leukotriene release, adhesion molecules, and cytokines. However in the last decade, olopatadine saw two other competitors, bepotastine and alcaftadine [1,11]. Both are dual-acting agents, the former has a high affinity for the H1 receptor, has rapid onset, and lasts up to 8 h. Alcaftadine though stands apart from both olopatadine and bepotastine as it possesses an affinity ten times greater to both H1 and H2 receptors, than its predecessors [4,9,11]. It also has some affinity to the H4 receptors expressed on mast cells, leukocytes, and CD4+ cells, therefore also inhibiting eosinophils.
Ophthalmic steroids are often concomitantly prescribed along with dual-activity agents in the clinical situation where the patient reports excessive and persistent signs and symptoms that severely interfere with quality of life. They are commonly used in ‘burst’ treatment similar to oral steroids for asthmatics, or when the presentation is significant. The ester-based steroid, loteprednol etabonate (0.2% Alrex, 0.5% Lotemax suspension, gel, both Bausch and Lomb), is the preferred agent for allergic conjunctivitis. This steroid is metabolized more efficiently therefore reducing the risk of adverse side-effects.
Currently, there are new topical steroids being researched. Mapracorat is in phase II trials and may be safer for long-term use compared with its older counterparts as it does not cause as much of an increase in intraocular pressure . Loteprednol is a retrometabolically engineered C20 ester-based corticosteroid that undergoes rapid metabolism into inactive metabolites and thus have decreased risk of causing elevated intraocular pressure (IOP) . Loteprednol 0.02% is indicated for the treatment of seasonal allergic conjunctivitis with only 1% of patients demonstrating an IOP rise of at least 10 mmHg without any correlation to cataract development. Ketone-based topical steroids such as prednisolone acetate 1%, prednisolone phosphate 1%, and dexamethasone 0.1% can be prescribed for severe cases of allergic conjunctivitis but are associated with more ocular adverse effects.
Owing to the risk of cataract development and increased intraocular pressure, ophthalmic steroids should be used short term, in conjunction with dual-activity agents [4,5▪▪,16].
Topical nonsteroidal antiinflammatory drugs
Topical nonsteroidal antiinflammatory drugs (NSAIDs) prescribed for ocular allergies include ketorolac tromethamine, diclofenac sodium, and nepafenac. Of note, only ketorolac was approved for seasonal allergic conjunctivitis. Other formulations have shown efficacy in treating vernal keratoconjunctivitis (VKC). Although not prescribed as often as other ocular allergy treatments, they are often used when the more popular dual-acting agents and corticosteroids have failed. NSAIDs work by inhibiting the cyclooxygenase pathway, and thus blocking prostaglandin production .
Decongestants present with the risk of rebound hyperemia and conjunctiva medicamentosa. Owing to this phenomenon, there is a need for other vasoconstrictors. Since 2017 brimonidine, which was previously approved for glaucoma, was approved for treatment of ocular redness as well [18,19]. Brimonidine is a highly selective α-2 receptor agonist and possesses a low-binding affinity for α-1 receptors. Four different trials reported low-dose brimonidine as safe and effective in treating conjunctival hyperemia, with rapid onset and duration of up to 8 h .
Immunotherapy includes both sublingual immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT) [4,13,20,21]. This method of treating ocular allergies is the only one that provides the patient with long-term relief after the course of treatment is completed. Although both SCIT and SLIT are effective, recent research suggests that SCIT may be more beneficial for patients who require polysensitization. SLIT significantly improves symptoms of ocular allergies because of ragweed, grass pollen, and dust mite [2,4].
Other than SLIT and SCIT, epicutaneous and intralymphatic immunotherapies have also shown symptom improvement when exposed to the allergen following treatment [5▪▪,13].
Topical immunomodulators are currently used in severe allergic ocular conditions, such as VKC and AKC. The two most well studied and used at the moment are cyclosporine A and tacrolimus, the former is also indicated for dry-eye syndrome. Both immunomodulators ultimately work by inhibiting T-cell activation. The success of cyclosporine A and tacrolimus has opened the door to research other immunomodulatory agents; however, their use is limited by their low water solubility and lipophilic nature [4,7,13].
Since 1973, there has been research involving cannabis and its receptors, cannabinoid receptor 1 (CB1) and CB2 as possible targets of treatments for different ocular diseases including anterior surface inflammatory disorders . CB1 is expressed in corneal cells and when activated leads to a decrease in inflammation. Although at first look this seems like a promising treatment, cannabinoid extracts have a very lipophilic profile and therefore do not penetrate the surface easily for the potential of intraocular inflammation but may possess properties that would maximize their effect on allergic inflammation , but present oil-based extract formulations have been reported to cause irritation of the ocular surface [23▪].
The immunobiological modulation of allergic disorders has primarily focused on asthma and atopic dermatitis. Omalizumab has repeatedly been shown to be successful in treatment of treatment-resistant VKC and AKC; however, it is still not approved for use in allergic eye disease [1,24–31]. Dupilumab, an IL-4 and IL-13 pathway inhibitor, has been reported to be associated with inflammation of the anterior conjunctiva and hyperemia of the limbus which is reported as a conjunctivitis [1,22,32]. Preexisting allergic conjunctivitis appears to be a risk factor and has been reported to respond to topical corticosteroid treatment or off-label tacrolimus 0.03% eye ointment. Mepolizumab, reslizumab, or benralizumab (anti-IL-5 biologic agents) have not been studied in the context of allergic conjunctivitis.
The future of ocular allergy treatment is currently in the making as both novel research is taking place simultaneously with efforts to reformulate available drugs.
Although topical ophthalmic solutions are the most convenient treatment, the eye's anatomy and physiology leads to decreased bioavailability of the drugs. To overcome these limitations, there is much research invested in ocular drug-delivery systems.
In addition to the methods discussed throughout the article, nanotechnology is another approach being taken. These include nanomicelles, nanoparticles, nanosuspensions, and dendrimers. All increase bioavailability because of their unique characteristics .
Nanomicelles’ small size and hydrophilic corona allow for an aqueous solution and enhanced bioavailability. Nanoparticles are nanosized colloidal carriers composed of lipids, proteins, and natural or synthetic polymers. Seeing as they are rapidly cleared from the precorneal pocket, nanoparticles with mucoadhesive properties are being developed. Nanosuspensions are stabilized by polymers or surfactants. Several studies have already proven increased ocular bioavailability of glucocorticoids as a nanosuspension formula .
Other research is focusing on options such as edible rice, vaccines, mechanical barrier gels, and even probiotics.
Although antihistamines remain the gold-standard for treatment of allergic conjunctivitis, this is still an exciting time in development of novel drugs and drug delivery. The approval of cetirizine as an ophthalmic solution, and the creation of the contact lens containing antihistamines, has opened the door to convenient and longer lasting treatments.
Furthermore, evolving research is focusing on treating ocular allergies via different mechanisms while optimizing relief and decreasing side-effects. This combination brings with it hope that not only will quality of life improve because of symptom relief but also thanks to drug delivery and efficacy.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
1. Dupuis P, Prokopich C, Hynes A, Kim H. A contemporary look at allergic conjunctivitis
. Allergy, Asthma Clin Immunol 2020; 16:5.
2. Carr W, Schaeffer J, Donnenfeld E. Treating allergic conjunctivitis
: a once-daily medication that provides 24-hour symptom relief. Allergy Rhinol 2016; 7:107–114.
3. Bielory L. Allergic and immunologic disorders of the eye. Part II: ocular allergy
. J Allergy Clin Immunol 2000; 106:1019–1023.
4. Ackerman S, Smith LM, Gomes PJ. Ocular itch associated with allergic conjunctivitis
: latest evidence and clinical management. Ther Adv Chronic Dis 2016; 7:52–67.
5▪▪. Bielory L, Delgado L, Katelaris CH, et al. ICON: diagnosis and management of allergic conjunctivitis
. Ann Allergy, Asthma Immunol 2020; 124:118–134.
6. Trangsrud AJ, Whitaker AL, Small RE. Intranasal corticosteroids for allergic rhinitis. Pharmacotherapy 2002; 22:1458–1467.
7. Shaker M, Salcone E. An update on ocular allergy
. Curr Opin Allergy Clin Immunol 2016; 16:505–510.
8. Bielory BP, Shah S, Bielory L. Understanding ophthalmic antihistamines
and histamine receptors. Rev Cornea Cont Lens. March 15, 2016, pg. 18–23
9. Leonardi A, De Dominicis C, Motterle L. Immunopathogenesis of ocular allergy
: a schematic approach to different clinical entities. Curr Opin Allergy Clin Immunol 2007; 7:429–435.
10. Meier E, Torkildsen G, Gomes P, Jasek MC. Phase III trials examining the efficacy of cetirizine ophthalmic solution 0.24% compared to vehicle for the treatment of allergic conjunctivitis
in the conjunctival allergen challenge model. Clin Ophthalmol 2018; 12:2617–2628.
11. Wade L, Bielory L, Rudner S. Ophthalmic antihistamines
and H1–H4 receptors. Curr Opin Allergy Clin Immunol 2012; 12:510–516.
12. Bartra J, Mullol J, Montoro J, et al. Effect of bilastine upon the ocular symptoms of allergic rhinoconjunctivitis. J Investig Allergol Clin Immunol 2011; 21: (Suppl 3): 24–33.
13. Bielory L, Schoenberg D. Ocular allergy
. Curr Opin Allergy Clin Immunol 2019; 19:495–502.
14. Malhotra RP, Edward M, Torkildsen G, et al. Safety of cetirizine ophthalmic solution 0.24% for the treatment of allergic conjunctivitis
in adult and pediatric subjects. Clin Ophthalmol 2019; 13:403–413.
15. Pall B, Gomes P, Frank Y, Torkildsen G. Management of ocular allergy
itch with an antihistamine-releasing contact lens. Cornea 2019; 38:713–717.
16. Spampinato S, Baiula M, Bedini A, et al. Mapracorat, a selective glucocorticoid receptor agonist, causes apoptosis of eosinophils infiltrating the conjunctiva in late-phase experimental ocular allergy
. Drug Des, Dev Ther 2014; 8:745–757.
17. Comstock TL, Sheppard JD. Loteprednol etabonate for inflammatory conditions of the anterior segment of the eye: twenty years of clinical experience with a retrometabolically designed corticosteroid. Expert Opin Pharmacother 2018; 19:337–353.
18. Ackerman SL, Torkildsen GL, McLaurin E, Vittitow JL. Low-dose brimonidine for relief of ocular redness: integrated analysis of four clinical trials. Clin Exp Optom 2019; 102:131–139.
19. Mclaurin E, Cavet ME, Gomes PJ, Ciolino JB. Brimonidine ophthalmic solution 0.025% for reduction of ocular redness. Optometry Vis Sci 2018; 95:264–271.
20. Calderon MA, Penagos M, Sheikh A, et al. Sublingual immunotherapy for treating allergic conjunctivitis
. Cochrane Database Syst Rev 2011; null:CD007685.
21. Yang J, Zhang L, Zhao Z, Liao S. Sublingual immunotherapy for pediatric allergic conjunctivitis
: a meta-analysis of randomized controlled trials. Int Forum Allergy Rhinol 2018; 8:1253–1259.
22. Assimakopoulou M, Dionysios P, Nterma P, Pharmakakis N. Immunolocalization of cannabinoid receptor type 1 and CB2 cannabinoid receptors, and transient receptor potential vanilloid channels in pterygium. Mol Med Rep 2017; 16:5285–5293.
23▪. Tanaka T, Atsuhiko L, Hiroshi H, Shoji H. Potential beneficial effects of wine flavonoids
on allergic diseases. Diseases 2019; 7:8.
24. Jay WM, Green K. Multiple-drop study of topically applied 1% 9-tetrahydrocannabinol in human eyes. Arch Ophthalmol 1983; 101:591–593.
25. de Klerk TA, Sharma V, Arkwright PD, Biswas S. Severe vernal keratoconjunctivitis successfully treated with subcutaneous omalizumab. J AAPOS 2013; 17:305–306.
26. Occasi F, Duse M, Nebbioso M, et al. Vernal keratoconjunctivitis treated with omalizumab: a case series. Pediatr Allergy Immunol 2017; 28:503–505.
27. Callet M, Stolowy N, Zanin E, Denis D. Interêt de l’omalizumab dans le traitement de la kérato-conjonctivite vernale sévère. Quand une kérato-conjonctivite vernale résiste aux traitements classiques [Omalizumab for severe vernal keratoconjunctivitis]. J Fr Ophtalmol 2018; 41:e499–e500.
28. Simpson RS, Lee JK. Omalizumab as single-dose therapy for vernal keratoconjunctivitis. Ann Allergy Asthma Immunol 2019; 122:119–120.
29. Santamaría L, Sánchez J. Eficacia a largo plazo del omalizumab en pacientes con queratoconjuntivitis vernal resistente a tratamiento convencional [Long-term efficacy of omalizumab in patients with conventional treatment-resistant vernal keratoconjunctivitis]. Rev Alerg Mex 2018; 65:192–196.
30. Heffler E, Picardi G, Liuzzo MT, et al. Omalizumab treatment of vernal keratoconjunctivitis. JAMA Ophthalmol 2016; 134:461–463.
31. Sánchez J, Cardona R. Omalizumab. An option in vernal keratoconjunctivitis? Allergol Immunopathol (Madr) 2012; 40:319–320.
32. Taillé C, Doan S, Neukirch C, Aubier M. Omalizumab for severe atopic keratoconjunctivitis. BMJ Case Rep 2010; 2010:BCR0420102919.
33. Wollenberg A, Lieneke A, Thurau S, et al. Conjunctivitis occurring in atopic dermatitis patients treated with dupilumab: clinical characteristics and treatment. J Allergy Clin Immunol Pract 2018; 6:1778.e1–1780.e1.
34. Patel A. Ocular drug delivery systems: an overview. World J Pharmacol 2013; 2:47.