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Immunotherapy: Does it play a role in ocular allergy?


Numerous clinical trials are under way that may help to define the role of immunotherapy in ocular allergy.

Numerous clinical trials are under way that may help to define the role of immunotherapy in ocular allergy.


By Paul Gomes

Therapeutic approaches to ocular allergic disease are at a crossroad. Topical and systemic antihistamines have evolved to once-daily treatments that provide effective symptomatic relief to a large segment of the population, but for another group-perhaps as many as one-third of the 40 million people in the United States with seasonal or perennial allergy-none of the current treatments provide consistent relief.

One therapeutic strategy common outside the United States is immunotherapy, a technique of re-training or desensitizing the immune system so that responses to common allergens such as pollen, animal dander, or dust mites are attenuated. Multiple immunotherapy trials are under way or recently completed in the United States, so it is a good time to consider this new technique and how it might impact therapy of allergic conjunctivitis.

Diseases such as atopic dermatitis, rhinitis, and AC are a related group of disorders that-together with asthma-comprise what has been referred to as the atopic march. All of these conditions involve development of a type-2 regulatory T-cell response to common environmental allergens, leading to an inappropriate IgE 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 T-regs and the non-allergenic type-1 T-cells.

Although this desensitization process is not completely understood, suppression of allergen-specific IgE production is also thought to be important in immunotherapy.1



SCIT and SLIT modalities

Any type of immunotherapy involves a repeated presentation of small amounts of antigen. In the United States, subcutaneous injection (SCIT) has been the method of choice for these treatments. The protracted nature of the treatment regimes has limited this therapy to the most severely allergic patients.

In contrast, European physicians have used both oral and topical delivery of antigen for many years. Both of these treatment modalities have shown similar efficacy and safety profiles when compared with SC antigen delivery. Recent large-scale trials in the United States have focused on sublingual allergen delivery (SLIT), a modality that has the potential to expand the use of immunotherapy to a much greater patient population.2

A sample of recent trials in the United States is summarized in Table 1. Note that few of these studies use any primary measures of allergic conjunctivitis as endpoints.

There is a good deal of misinformation surrounding the use of immunotherapy, particularly with respect to its safety profile. In a recent meta analyses of SLIT that included thousands of subjects over a wide range of allergen doses and delivery protocols, there are only a handful of reported incidents of anaphylaxis.

In addition, these trials have established that significant 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 other hand, 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 address specifically the efficacy of SLIT for AC.

Patients with allergies commonly experience a spectrum of symptoms that includes ocular itching, hyperemia, and chemosis. In fact, more than 80% of allergy sufferers report experiencing some ocular symptomology. Despite this, several of the recent trials have only limited measures of ocular symptoms often included in score based upon “gritty eyes or watery eyes.” None of the scores appear to include direct measures of ocular itching, the hallmark symptom of AC.3

Of greater impact is the lack of a positive comparator group, such as antihistamine or steroid therapy. Most studies 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.4



A measure of efficacy

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 addition, conjunctival allergen challenge protocols such as the CAC are validated metrics that have been used in FDA assessment of AC therapies. So it is hard to understand why metrics like the CAC have not been employed to develop immunotherapeutics.

The few studies that include conjunctival challenge data suggest that ocular itching may be a more sensitive measure of efficacy. In recent reports, ocular itching was reduced 30% to 48% from placebo, whereas the threshold for conjunctival response to allergen provocation was significantly increased.5

When compared with the best reported nasal or ocular symptom score improvements of 24% to 28%, it seems as if some of these early studies may have omitted a valuable endpoint from their trials. The medical community will know more when the decisions of the FDA on this new approach to allergic diseases such as AC are announced later this year.


1. Fujita H, Soyka MB, Akdis M, Akdis CA. Mechanisms of allergen-specific immunotherapy. Clin Transl Allergy. 2012;2:2.

2. Nelson HS. Is sublingual immunotherapy ready for use in the United States? JAMA 2013:309;1297-1298.

3. Maloney J, Bernstein DI, Nelson H, et al. Efficacy and safety of grass sublingual immunotherapy tablet, MK-7243: a large randomized controlled trial.Ann Allergy Asthma Immunol. 2014;112: 146-153.

4. Abelson MB. Comparison of the conjunctival allergen challenge model with the environmental model of allergic conjunctivitis.Acta Ophthalmol Scand Suppl. 1999;228:38-42.

5. Calderon MA, Penagos M, Sheikh A, Canonica GW, Durham SR. Sublingual immunotherapy for allergic conjunctivitis: Cochrane systematic review and meta-analysis. Clin Exp Allergy. 2011;41:1263-1272.


Paul Gomes is vice president, allergy at Ora Inc., Andover, MA.



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