Topical antihistamines, including antihistamine/mast cell stabilizers, remain the agents of choice for treatment of allergic conjunctivitis, especially with the availability of once-daily dosing. Beyond these, there remains a need for more effective treatments for AKC and VKC and even for those with the more severe forms of PAC that are often less responsive to traditional therapies. Although topical and systemic steroids remain the treatment of choice for such conditions, a number of recent trials are testing alternative therapies that may avoid adverse steroid effects. For example, a recent meta-analysis confirmed that the anti-immunoglobulin E monoclonal antibody omalizumab (Novartis, Basel, CHE, Switzerland) was efficacious in patients with severe rhinitis or rhinoconjunctivitis without significant adverse effects. Although such treatments may not be cost-effective, a host of biological targets, such as TNF-α, IL-4, and IL-13, may represent valuable treatment targets for future small-molecule therapies.
Many trials have tested calcineurin inhibitors (cyclosporine, tacrolimus) for VKC, including several that are currently underway (NCT02057822, NCT01751126). Although physicians in Europe have been using these compounds to treat VKC for decades, controlled trial data are still lacking. A recently published Japanese trial did present promising data on tacrolimus for chronic allergy with proliferative lesions or corneal involvement. The study was observational and did not include a placebo group, but did include cohorts of patients unresponsive to cyclosporine or steroid therapy. Both groups showed significant improvement in both signs and symptoms of chronic inflammation within a month of initiating therapy. Adverse effects were minimal, with 3.2% of 1436 patients reporting a burning discomfort upon application. A formulation of cyclosporine, Restasis (Allergan), is the only Food and Drug Administration-approved medication with an indication for dry eye; this, as well as the success of calcineurin inhibitors in treating VKC suggests that other dry eye treatments might also be appropriate for relief of chronic allergy. This idea was tested in a trial of rebamipide (Otsuka Pharmaceuticals, Tokyo, Japan), a topical compound approved in Japan for dry eye, for patients with either AKC or VKC.
These observations highlight a growing awareness that dry eye and ocular allergy, especially chronic allergy, share a common inflammatory mechanism that suggests a potential for dual-purpose or multipurpose ocular anti-inflammatory agents. In addition, it is clear that the two conditions exhibit a significant comorbidity that may provide a clinical foothold in developing treatments for both conditions. The relationship between dry eye and allergic conjunctivitis was explored in another recent study that showed that conditions normally associated with enhanced dry eye symptomology that are elicited by a controlled adverse environment can also exacerbate signs and symptoms of allergic conjunctivitis (Fig. 1). Recent discussion of new therapies for allergy has been dominated by immunotherapy, a technique of retraining or desensitizing the immune system so that responses to a specific allergen such as pollen, animal dander, or dust mites are attenuated. This strategy for desensitization of the immune system to allergen exposure has been used for decades, but recent efforts have sought to standardize therapeutic protocols and, in the USA, have particularly focused on sublingual allergen delivery. Multiple immunotherapy trials are underway or have been recently completed in the USA; the first oral agents for the treatment of grass allergy (Oralair, Stallergene Antony, France; Grastek, Merck, White House Station, New Jersey, USA) and ragweed allergy (Ragwitek, Merck) were approved by the Food and Drug Administration in 2014 (http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm393820.htm). With this in mind, it seems a good time to consider this new technique and how it might impact the therapy of allergic conjunctivitis.
Adverse environments associated with dry eye can exacerbate signs and symptoms of allergic conjunctivitis. Patients (n=18; nine in each group) with a history of ocular allergy and dry eye were randomly assigned to two groups; one group was subjected to a 30-min exposure to a controlled adverse environment (CAE), followed by a 30-min recovery, and conjunctival allergen challenge (CAC). When signs and symptoms of allergic conjunctivitis were compared between this CAE–CAC and control patients who were not subjected to CAE, all allergic conjunctivitis metrics were increased, including itch and redness, where the increase was statistically significant .
Allergic diseases such as allergic rhinitis and allergic conjunctivitis involve the development of a type-2 regulatory T-cell response to common environmental allergens, leading to an inappropriate immunoglobulin E production and immunological sensitization. When subsequently exposed to the allergenic culprit, these antibodies can initiate mast cell degranulation and the entire sequela of an allergic response. If the same antigen is exposed to dendritic cells or other antigen-presenting cells at low concentrations, it is possible to initiate a shift in the regulatory balance between the type-2 regulatory T-cells and the nonallergenic type-1 T-cells. Although this desensitization process is not completely understood, suppression of allergen-specific immunoglobulin E production is also thought to be important in immunotherapy.
Recent trials have focused on the delivery of allergen by a sublingual immunotherapy (SLIT) formulation rather than the subcutaneous injection route that has been the method of choice in the USA. The protracted nature of the injection regimes had limited this therapy to the most severely allergic patients, but the most recent studies suggest a similar efficacy for oral subcutaneous delivery of antigen. Recent large-scale trials in the USA have focused on SLIT therapy for grass and ragweed allergies, and trials are underway using allergens from dust mites. Studies with other perennial and seasonal allergens are likely to follow, and although there are no available studies comparing sublingual allergen delivery with subcutaneous methods, there does seem to be fewer overall adverse effects. A sample of recent trials in the USA is summarized in Table 1 . Note that few of these studies use any primary measures of allergic conjunctivitis as endpoints.
Concerns about immunotherapy safety and the risk of anaphylaxis were addressed in recent meta-analyses of SLIT that included thousands of patients over a wide range of allergen doses and delivery protocols. These studies concluded that there was very little risk of anaphylaxis associated with the treatment. In addition, evidence suggests that relief from signs and symptoms of allergy can develop with weeks of therapy initiation, and that this relief is sustained even after a discontinuation of allergen. On the contrary, despite the large number of trials, there still seems considerable debate over dosing issues. In addition, the high numbers of recent trials for grass, ragweed, and dust mite allergens have been unable to specifically address the efficacy of SLIT for allergic conjunctivitis.
Patients with allergies commonly experience a spectrum of symptoms that includes ocular itching, hyperemia, and chemosis. More than 80% of allergy sufferers report experiencing some ocular symptomology. Despite this, immunotherapy trials have only limited measures of ocular symptoms often included in score based upon 'gritty eyes or watery eyes'. None of the scores appears to include direct measures of ocular itching, the hallmark symptom of allergic conjunctivitis. Despite this limitation, all of the newly approved SLIT therapies include an indication for use as 'an allergen extract indicated as immunotherapy for treatment of grass pollen-induced allergic rhinitis with or without conjunctivitis' (http://www.fda.gov/downloads/BiologicsBloodVaccines/Allergenics/UCM393184.pdf).
To date, there are no head-to-head studies comparing any immunotherapy agents to a positive comparator group such as antihistamine or steroid therapy. Most clinical trials do include rescue drug usage (either systemic, nasal, or ocular) as a secondary endpoint, but this does not provide a direct comparison between immunotherapy and established allergy treatments. This study design may be a reflection of the low statistical power inherent in all environmental trials.
Unlike treatments for allergic rhinitis, therapies targeted to allergic conjunctivitis typically achieve regulatory approval using controlled allergen challenge protocols such as the CAC, with or without additional environmental trials. Allergen challenge has been used to measure efficacy of allergen desensitization, and can provide an objective measure of the treatment effects on either nasal or ocular symptoms. In several trials, a conjunctival challenge component has been included as a secondary endpoint. Such measures are attractive as alternative or complementary assessments of treatment efficacy; for example, one study examining the specificity of immunotherapy showed a 16–31-fold increase in the threshold for conjunctival response to allergen provocation. This study also highlighted a critical distinction between SLIT and more traditional therapeutics: immunotherapy provides protection against a single allergen, whereas antihistamines, mast cell stabilizers, and corticosteroids act to modify allergic responses to all allergens. Future refinement of endpoints and outcome assessments will be critical in the use of SLIT as a therapy for allergic conjunctivitis going forward.