Sublingual immunotherapy: A new option for allergy patients

Many clinicians and pet owners are familiar with allergen-specific immunotherapy (ASIT)—commonly referred to as allergy injections or allergy shots—for the treatment of atopic dermatitis in dogs and cats. The newest variation on this treatment is orally administered ASIT called sublingual immunotherapy (SLIT)—or allergy drops. SLIT is administered through a metered pump dispenser that delivers a few drops of allergen solution onto the mucosa under and around the tongue (Figure 1).

1. Sublingual immunotherapy formulations (allergy drops) are administered by using small, metered pump bottles that dispense a small volume of allergen solution onto the oral mucosa. Here, the drops are administered to William. This client-friendly method is widely used in Europe to treat allergic respiratory disease and, more recently, atopic dermatitis in people.1,2 It has recently become available for animal use in the United States.

The potential lifelong benefits of ASIT—whether given through injections or drops—make it a preferred treatment for atopic dermatitis that should be discussed with owners early in treatment.

ALLERGY SHOTS VS. DROPS

There are many similarities between SLIT and allergy injections. Like injections, SLIT formulations are typically supplied in three bottles of increasing concentration. The cost of SLIT vs. injections is about the same, typically costing a client $40 to $50 a month. Concurrent medications (e.g. antihistamines, corticosteroids, cyclosporine) do not appear to interfere with the efficacy of injections or drops and are often given during the initial few weeks to months of immunotherapy treatment, while waiting for the injections or drops to become effective.

Practical differences include the specific ingredients: SLIT is not merely an oral administration of the saline-based allergy injection mixture. It is formulated differently, and commercial preparations typically include proprietary ingredients to stabilize the allergens and promote mucosal absorption. Depending on the supplier, stabilizers may allow for the addition of protease-containing mold allergens to the mixture and sometimes for room-temperature storage.

The mechanism by which SLIT works differs from that of injection ASIT, involving the absorption of allergens through the oral mucosa with uptake and processing by specialized oromucosal dendritic cells, which direct the immune system toward immunologic tolerance of the relevant allergen.3

Another practical difference is administration frequency. SLIT formulations are typically administered every day, often several times a day, for the duration of therapy with no tapering.

Since both allergy injections and allergy drops are effective, selection for individual patients can be made mostly based on client factors (see "Shots or drops? Considerations when selecting injection vs. sublingual ASIT for dogs").

EVIDENCE OF EFFICACY

Studies of SLIT in dogs are only just being reported and largely consist of uncontrolled trials. A small, open trial of atopic dogs with dust mite allergy treated with SLIT reported 80% clinical benefit. The benefit was usually accompanied by measurable immunologic changes, including significant increases in allergen-specific IgG and decreases in allergen-specific IgE.4,5

Another study reported some SLIT efficacy in a laboratory model with sensitized beagle dogs, including significant changes in antiallergic cytokines such as transforming growth factor beta and interleukin-10 in treated animals.6

In my clinical experience in an open trial with a specific product (Allercept Therapy Drops—Heska), about 60% of dogs with atopic dermatitis that have not been treated with ASIT previously will have substantial improvement of their clinical signs after being treated with this formulation, as judged by veterinarian evaluation of response.7

The response rate for dogs that previously failed to respond adequately to ASIT may also be substantial. In these open trials, about 50% of dogs that were "shot failures" because of lack of efficacy, difficulty with administration, or anaphylactic reactions were successfully treated with SLIT.7 That is consistent with experimental evidence that shows that the mechanism of SLIT is different than that of injection immunotherapy.3,8

ADVANTAGES AND DISADVANTAGES

One big advantage of SLIT is the ease of administration. Although many owners do not mind giving injections to their pets, most do not relish it and are happy to be presented with an alternative. Most dogs accept SLIT administration easily, even viewing it as a treat, which increases compliance. However, successful SLIT requires faithful daily administration, and owners with busy schedules may find it more convenient to give a less frequent injection.

Data from a supplier (including several thousand dogs) indicate that adverse reactions to allergy drops may occur in about 4% of dogs.9 Nearly all of these reactions are mild and temporary and almost never require cessation of treatment. Most occur soon after starting treatment but disappear within a few days or a week of continued treatment.

The most common reaction is transient worsening of clinical signs, usually increased pruritus. A few dogs may rub or scratch at their mouth after administration, perhaps analogous to the oral itch that some human SLIT patients experience. Occasional stomach upset or vomiting has been observed in a few dogs.

In people, anaphylactic reactions to SLIT are rare to nonexistent, and SLIT can be given to people with a history of reaction to allergy injections. In the experience at the University of Wisconsin's School of Veterinary Medicine, the same is true in dogs. We have safely treated numerous patients with SLIT that have had anaphylactic reactions to allergy injections.

PROTOCOLS FOR SLIT IN DOGS

Initial diagnostic and allergen testing

In general, do what you have always done. The process of diagnosing atopic dermatitis through diagnostic testing to eliminate other possibilities and follow-up allergy testing are the same whether you plan to treat with SLIT or allergy injections. Any combination of serologic or intradermal testing techniques may be used to establish the individual sensitivities of each patient.

Allergen selection and formulation

After careful testing, the principles for choosing the allergens in the prescription are exactly the same as those used when choosing allergens for injection ASIT mixtures. SLIT formulation suppliers (Table 1) are familiar with these principles and will provide a suggested formulation based on the allergy test results for each patient.

Table 1: Sublingual immunotherapy veterinary formulation suppliers

Dosing

Treatment involves a series of three bottles of escalating concentration. The allergen solution should remain in contact with the oral mucosa for as long as possible. People are instructed to hold the solution under their tongue for one minute before swallowing. Obviously, we cannot request the same of dogs, but it is important that the solution is dispensed directly into the oral cavity, not in food, and that the dogs refrain from eating or drinking for five to 10 minutes after the dose is given.

Multiple daily administrations are required for efficacy in people, and our clinical group strongly recommends that owners be counseled to administer the allergy drops twice daily, every day. If they forget to give a dose in the morning, they should give one in the afternoon and one before bed. This twice-daily dosing schedule is indefinite for the duration of therapy with no tapering. It should be mentioned that each SLIT formulation supplier has established its own protocol for allergen concentrations, dosing volumes, frequencies, and schedules; comparative studies of different protocols have not been performed.

It is easy to switch a patient from injections to drops. Three possible situations exist.

1. If the patient has had no response to allergy injections, I recommend the standard protocol, starting SLIT with the lowest-concentration bottle and escalating.

2. If the patient is stable and has been doing well with the injections (perhaps the owner is just tired of giving them), you can typically start directly with the maintenance vial of SLIT, with no need for the escalation phase.

3. If the patient is being switched to drops because of an adverse reaction to allergy injections, I recommend cautious administration of the lowest-concentration vial at first. If there seems to be any adverse reaction or worsening, reduce the concentration even further.

At this time, the ideal total duration of treatment is not known in dogs. In people, daily administration is continued for two to five years. After this time, if the patient is stable, treatment can be discontinued, and the effect appears to be permanent in nearly all cases. Whether that is true in dogs is unknown.

Follow-up evaluations

As with injection ASIT, it is important to re-evaluate patients receiving SLIT on a regular basis (e.g. after three, six, and 12 months of treatment, which is what we use in our clinical group). My subjective clinical impression is that response to SLIT often occurs quite rapidly—some dogs are improved three months after starting SLIT treatment, and most that will respond show at least some improvement, if not substantial improvement, after six months of treatment.

Adverse reactions

If any adverse reactions occur or persist, it may require lowering the allergen dose. You should contact the SLIT supplier for specific instructions as to how to accomplish this for that specific formulation.

CONCLUSION

There is much still to learn about this new allergy treatment. Even in human medicine, which has been using SLIT for more than 40 years, there is still debate about the optimal dosing schedule. I look forward to further studies in dogs that will provide additional evidence of efficacy based on controlled trials, will compare dosing regimens, and perhaps will compare this therapy more directly to ASIT administered by injection.

Editors' note: Dr. DeBoer is a consultant to Heska, manufacturer of Allercept Therapy Drops, but has no financial interest in any sublingual immunotherapy product.

Douglas J. DeBoer, DVM, DACVD Department of Medical Sciences School of Veterinary Medicine University of Wisconsin Madison, WI 53706

REFERENCES

1. Meadows A, Kaambwa B, Novielli N, et al. A systematic review and economic evaluation of subcutaneous and sublingual allergen immunotherapy in adults and children with seasonal allergic rhinitis. Health Technol Assess 2013;17:1-322.

2. Burks AW, Calderon MA, Casale T, et al. Update on allergy immunotherapy: American Academy of Allergy, Asthma & Immunology/European Academy of Allergy and Clinical Immunology/PRACTALL consensus report. J Allergy Clin Immunol 2013;131:1288-1296.

3. Moingeon P, Mascarell L. Induction of tolerance via the sublingual route: mechanisms and applications. Clin Dev Immunol 2012;2012:623474.

4. DeBoer DJ, Verbrugge M, Morris M. Pilot trial of sublingual immunotherapy in mite-sensitive atopic dogs (abst). Vet Dermatol 2010;21:325.

5. DeBoer D, Verbrugge M, Morris M. Changes in mite-specific IgE and IgG levels during sublingual immunotherapy (SLIT) in dust mite-sensitive dogs with atopic dermatitis (abst), in Proceedings. Eur Soc Vet Dermatol Meet 2010.

6. Marsella R, Ahrens K. Investigations on the effects of sublingual immunotherapy on clinical signs and immunological parameters using a canine model of atopic dermatitis: a double-blinded, randomized, controlled study (abst). Vet Dermatol 2012;23(Suppl 1):66.

7. DeBoer D, Morris M. Multicentre open trial demonstrates efficacy of sublingual immunotherapy in canine atopic dermatitis (abst). Vet Dermatol 2012;23(Suppl 1):65.

8. Ozdemir C. An immunological overview of allergen specific immunotherapy—subcutaneous and sublingual routes. Ther Adv Respir Dis 2009;3:253-262.

9. Heska, Loveland, Colo: Personal communication, 2013.