Although winter can be the season of relief for many who are affected by the allergens that accompany the warmer months of the year, for others it provides no respite. Even worse, many of these patients know that winter allergies represent just one of four seasons of chronic, perennial allergic conjunctivitis. But patients with allergies in winter are an important population for those of us who are concerned with ocular allergy. Not only do they suffer with allergic symptomologies throughout the winter, but these are also the patients most likely to have the most severe responses to summer allergens as well. They’re also a population most likely to exhibit a resistance to the current therapies, so they represent a significant unmet therapeutic need. Effective treatments for these patients represent a holy grail of ocular therapeutics.
This month, we examine the attributes of our patients with perennial allergy, and review current and potential therapies that are designed to combat the chronic inflammation often associated with these individuals’ allergic response to persistent allergens in their environment.
Dust Mites and Animal Dander
Seasonal allergies such as hay fever are a boom-and-bust process, with symptoms rising and falling with the pollen counts for spring birch, summer grass and fall ragweed. The allergens of winter are, in contrast, omnipresent throughout the year: dust mites; cockroaches; and animal dander. Although avoidance may be a useful strategy for evading seasonal allergens, it is less likely to be achievable for perennial allergens, especially during the winter season. Decreased temperatures during the winter result in an increased amount of time indoors, less exchange of indoor air and, consequently, an increase in exposure to allergens. Use of aggressive hygiene approaches to minimize environmental exposure to these allergens (in particular, to dust mites) hasn’t proven to be an effective strategy.Sheikh A, Hurwitz B, Nurmatov U, et al. House dust mite avoidance measures for perennial allergic rhinitis. Cochrane Database Syst Rev 2010 Jul 7;7:CD001563. Thus, unlike the periodic spikes in seasonal allergens where avoidance can mitigate the level of exposure, the constant presence of perennial allergens results in continual priming of the allergic response, altering the immune reaction to future exposures and leading to a chronic inflammatory state.
In an acute response, high concentrations of allergens such as seasonal pollens trigger IgE-mediated degranulation of mast cells, causing a release of histamine and other pro-inflammatory mediators; these activate local histamine receptors and initiate the classic hyperemia and pruritus responses of AC. Antihistamines act as direct, pharmacological antagonists of these responses.Abelson MB, Shetty S, Korchak M, et al. Advances in pharmacotherapy for allergic conjunctivitis. Expert Opin Pharmacother 2015;16:8:1219-31. In contrast, a chronic AC elicited by continuous exposure to lower levels of allergen involves recruitment of secondary immune cells and a more extensive inflammatory response. Under these conditions physical barriers to allergens become compromised, and subsequent allergen exposures elicit an exacerbated response; proteolytic activity expressed by many common perennial antigens may play a role in this process.Hughes JL, Lackie PM, Wilson SJ, et al Reduced structural proteins in the conjunctival epithelium in allergic eye disease. Allergy 2006;61:1268-1274.
Recent evidence has also provided clues to prevalence of perennial parasite allergy: Significant similarities in epitopic-like regions (the epitope is the part of an antigen that’s recognized by the immune system) in parasite proteins and the most common allergenic protein domain families provide an explanation for off-target effects of IgE-mediated immune reactions.Tyagi N, Farnell EJ, Fitzsimmons CM, et al. Comparisons of allergenic and metazoan parasite proteins. PLOS Computational Biology DOI:10.1371/journal.pcbi.1004546 Oct 29, 2015. It may be that in the absence of infection, the highly specialized immune system components that have evolved to combat the effect of metazoan parasites switch to a collateral mode, becoming hyper-responsive to similar proteins such as dust mite group II allergens, Der p 2 and Der f 2 which, in turn, share structure homology with some components of grass expansin allergens.Kari O, Saari KM. Diagnostics and new developments in the treatment of ocular allergies. Curr Allergy Asthma Rep 2012;12:3:232-9.
Dust mites are the primary source of perennial indoor allergens.
Chronic mite and animal dander exposure is the most common source of perennial ocular allergies. Continuous activation and degranulation of mast cells activate cellular-mediated inflammation, structural cells of the corneal and conjunctival epithelium, vascular endothelial cells and fibroblasts. All of these components amplify initial responses and alter future immune responses by priming the antigen recognition sites on dendritic cells. Upregulation of adhesion molecules on the conjunctival epithelium results in infiltration of eosinophils, neutrophils and lymphocytes into the conjunctiva, leading to subsequent cascades of inflammatory mediators that characterize the persistent clinical inflammation of chronic allergic conjunctivitis. Perennial allergies thus can constitute a perfect storm of ocular distress, a vicious cycle in which the continuous exposure to allergens prevents reestablishment of a healthy conjunctival barrier.Bacon, AS, et al. Tear and conjunctival changes during the allergen-induced early- and late-phase responses. J Allergy Clin Immunol 2000;106:5:948-54.
Therapies
Currently, the only potent anti-inflammatory agents available to treat the chronic inflammation associated with PAC are topical corticosteroids, particularly glucocorticoids used for the treatment of severe or chronic ocular allergy. Although traditional topical glucocorticoids such as dexamethasone and prednisolone are known to be highly effective, the potentially serious adverse side effects of ocular hypertension, glaucoma and cataracts limit their use to short-term therapy for only the most severe forms of AC. It’s generally thought that a two to three week course of steroid therapy is required to break the chronic allergic cycle, but patients will be susceptible to bacterial or viral infections during that time. Newer-generation compounds are preferred over older GC agonists; these so-called “soft steroids” are designed to have a reduced biological half-life, allowing for a more precise timed delivery of therapeutic. For example, loteprednol has an ester bond replacement, causing it to be labile to conversion to an inactive metabolite, yielding a shorter therapeutic half-life and a more focused treatment window.Pavesio CE, Decory HH. Treatment of ocular inflammatory conditions with loteprednol etabonate. Br J Ophthalmol 2008;92:4:455-9.
One approach to improving current steroid therapy has been to dissect the anti-inflammatory effects of steroids away from their adverse side effects. This labor has borne fruit in the form of a class of drugs called selective glucocorticoid receptor agonists, or SEGRAs, which have been designed to target the glucocorticoid receptor without the collateral effects responsible for toxicity.Kato M. Beneficial pharmacological effects of selective glucocorticoid receptor agonist in external eye diseases. J Ocul Pharmacol Ther 2011;27:4:353-60. One such drug, Mapracorat, was shown in preclinical studies to selectively drive glucocorticoid receptor mediated anti-inflammatory effects with a diminished ability to promote the gene transactivation thought to be responsible for many adverse steroid effects such as ocular hypertension.Baiula M, Spampinato S. Mapracorat, a novel non-steroidal selective glucocorticoid receptor agonist for the treatment of allergic conjunctivitis. Inflamm Allergy Drug Targets 2014;13:5:289-98. Unfortunately, this selective efficacy has not been demonstrated in several clinical trials. But while interest in Mapracorat may have waned, the goal of a selective, safe glucocorticoid agonist remains.
The mast-cell hyperplasia observed in states of chronic PAC is known to be reduced only by repeated rather than acute steroid treatment, indicating that sustained drug release is critical to its efficacy.Nagata T. Effects of multiple dexamethasone treatments on aggravation of allergic conjunctivitis associated with mast cell hyperplasia. Biol Pharm Bull 2008;31:3:464-8. Thus, another avenue being explored for selectively targeting the glucocorticoid receptor is changing the drug pharmacokinetics through novel drug-delivery techniques. Ocular Therapeutix has developed an intracanalicular depot system that releases a lower yet sustained dose of dexamethasone. Preliminary studies in a guinea pig model for chronic allergy demonstrated that multiple dexamethasone treatments were effective in fnpressing both the chronic inflammatory score and mast-cell hyperplasia. These results led to its clinical program, and a successful clinical Phase II study. Phase III development of this depot steroid for chronic ocular allergy is imminent.
Non-steroidal anti-inflammatories are also approved for treatment of allergic conjunctivitis. They are less effective than antihistamines for acute disease, but several recent trials suggest they may be more effective if used in longer courses, comparable to steroid treatment regimes.Li Z, Mu G, Chen W, et al. Comparative evaluation of topical pranoprofen and fluorometholone in cases with chronic allergic conjunctivitis. Cornea 2013;32:5:579-82.
Immunomodulatory agents also provide a steroid-sparing alternative for allergic conjunctivitis, but have yet to obtain Food and Drug Administration approval for the treatment of ocular allergy.Mishra GP. Recent patents and emerging therapeutics in the treatment of allergic conjunctivitis. Recent Pat Inflamm Allergy Drug Discov 2011;5:1:26-36. Members of this drug class act by inhibiting calcineurin and have less-severe side effects than steroid treatment. Examples of immunomodulatory agents include cyclosporine A, pimecrolimus and tacrolimus. Although these agents are effective and have a better safety profile than steroids, they have had limited therapeutic success due to their low water solubility and lipophilic nature, resulting in challenging topical formulations and poor ocular penetration. Other treatments in the pipeline include the identification of new targets and sites of therapeutic intervention. For example, kinase inhibitors such as PRT2761 (Portola Pharmaceuticals) target the spleen tyrosine kinase that’s the link between IgE-antigen binding and subsequent events in the allergic cascade.
While antihistamines are thought of as therapy for acute allergy, newer generations have anti-inflammatory properties that may provide a higher efficacy for perennial allergy sufferers. The best example of this is alcaftadine, a long-acting histamine antagonist that has been shown to be clinically fnerior to the most-prescribed drug in this class, olopatadine.Chigbu DI, Coyne AM. Update and clinical utility of alcaftadine ophthalmic solution 0.25% in the treatment of allergic conjunctivitis. Clin Ophthalmol 2015;8;9:1215-25. A proposed mechanism underlying this fneriority was described in preclinical studies, where alcaftadine demonstrated an ability to reduce inflammatory cell infiltration through the stabilization of conjunctival epithelial tight junctions; it’s also been shown to antagonize multiple histamine receptor subtypes.,Ono SJ, Lane K. Comparison of effects of alcaftadine and olopatadine on conjunctival epithelium and eosinophil recruitment in a murine model of allergic conjunctivitis. Drug Des Devel Ther 2011;5:77-84. It’s been proposed that an added benefit of this front-line reinforcement might be a reduction in the ability of the allergen to enter and activate the allergic cascade within the ocular tissue.
Clinical Models
The difficulty of studying AC in humans has been a substantial hurdle in developing new agents, particularly those that target chronic inflammation.Abelson MB. Advances in pharmacotherapy for allergic conjunctivitis. Expert Opin Pharmacother 2015;16:8:1219-31. Seasonal trials that focus on a recapitulation of a natural setting are limited by unpredictable allergen levels and placebo effects. The clinical evolution of AC is unpredictable, and manifestations are dramatically modified by external stimuli, such as the specific type and prevalence of allergen. Uncontrollable intrinsic and extrinsic variables during a clinical trial such as sensitivity to allergen and comorbidities (intrinsic), allergen exposure and patient compliance (extrinsic) collectively contribute to a heterogeneous population with an unstable baseline for study. Also, the phenomenon of “placebo benefit” can have as much as a 70-percent effect on signs and symptoms due to dilution or washing away the allergen.Ousler GW. Methodologies for the study of ocular surface disease. Ocul Surf 2005;3:3:143-54.
The conjunctival allergen challenge model was developed for the evaluation of anti-allergic compounds to address these shortcomings.Abelson MB, Chambers WA, Smith LM. Conjunctival allergen challenge: A clinical approach to studying allergic conjunctivitis. Arch Ophthalmol 1990;108:1:84-8. Subjects are tested for ocular sensitivity by instilling allergen in the eye at increasing doses until a moderate to severe, but still modifiable, allergic response is produced. Originally designed to model acute allergy, the CAC model has been modified in order to target the chronic inflammatory response associated with PAC. To provoke the chronic inflammatory response, multiple doses of allergen challenge are delivered to invoke a late-phase allergic response and increase levels of cellular infiltrates. Thus, repetitive allergen challenge has provided a model for the study of the efficacy of anti-inflammatory therapeutics in subjects with chronically inflamed tissue. (Gomes et al. IOVS 2006;47:ARVO E-abstract 4978) This approach can be brought closer to real-world exposure in environmental chambers (such as the Ora Allergen Biocube) designed to provide precise control over allergen exposure in a more natural delivery modality.
Other Options
Research into mechanisms of chronic allergy and inflammation remains the key to improving therapies, but it’s also sometimes worthwhile to consider the tools at hand and ask, “Is there a better way?” An approach that’s been successful in treatment of glaucoma, for example, is combination therapy: pairing two drugs with different mechanisms of action to yield a therapeutic with greater efficacy and safety. Lower concentrations of each ingredient mean reduced adverse effects. With an improved understanding of the cells, mediators and immunological events that occur in chronic ocular allergy, we are in a better position to identify and explore potential combination therapies; perhaps a combined antihistamine-calcineurin inhibitor would provide the balance needed to treat the whole chronic allergy patient. We expect that some degree of balance between therapeutic development and clinical progress will provide the key to more effective treatments for winter allergies.
Dr. Abelson is a clinical professor of ophthalmology at Harvard Medical School. Mr. Gomes is vice president of allergy at Ora Inc. Dr. Slocum is a medical writer at Ora Inc.
