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Pamela A. Davol, 76 Mildred Avenue, Swansea, MA  02777-1620.
pdavol@labbies.com


Dermatologic (Skin) Disorders of the Dog:
A Multipart Series

Atopy (Environmental Allergies Affecting the Skin)

Atopy is a disorder by which dogs have a predisposition for developing antibodies to environmental allergens. Atopy is the most common disorder causing hypersensitive skin reaction in non-flea allergic patients presenting with dermatitis and accounts for up to 70% to 90% of all hypersensitive conditions. As such, atopy is significantly more prevalent than food allergy in the canine, which accounts for up to only 10% to 30% of hypersensitive conditions. Furthermore, although it has been found that up to 10% of dogs with atopy may also have food allergy, up to 80% of the dogs diagnosed with food allergy will also have atopy, thus accounting for the high rate of failure to treat food-allergy patients through manipulation of diet alone.

Cause: Dogs that develop atopic dermatitis have a predisposition for excessive production of immunoglobin E (IgE) antibodies. IgE antibodies are believed to be the primary immune defense against parasitic organisms, however, in humans and other animals including the dog, these antibodies are also responsible for producing allergic reactions. When a hypersensitive dog is first exposed to an environmental allergen such as pollen, molds, dander, etc., its immune system will begin to produce high levels of IgE antibodies that will accumulate in the tissues of the body. In humans, IgE is found predominantly in the respiratory and conjunctival mucus membranes, however, in dogs, IgE antibodies will locate predominantly to tissues comprising the skin. When the dog is re-exposed to the same allergen at a later time, IgE antibodies will bind to the allergen and activate release of histamines (a chemical that will attract other immune surveillance cells to the site of infection) from specialized blood-derived, immune cells called mast cells that are involved in the inflammatory response. Histamine release results in reddened and itchy skin consistent with symptoms of dermatitis. In some instances, some atopic dogs have been found to have non-reactive IgE antibodies, but demonstrated elevated levels of immunoglobin Gd (IgGd) antibodies. IgGd is a subset of IgG antibodies, a separate class of antibodies that predominantly circulates in the serum and is responsible for producing such conditions as anaphylactic reactions. Current studies are aimed at exploring the role of IgGd antibodies in the atopic disease process.

Interestingly, recent studies on IgE immune response, dermatologic hypersensitivity, and internal parasitism in humans inhabiting third-world countries have revealed potentially important implications as to why atopic disease in dogs has seemingly appeared to be progressively increasing over the last few decades. Researchers have found a curiously low incidence of allergy-related conditions (dermatitis, asthma, hayfever, etc.) in human populations that harbor high parasitic loads in comparison to parasite-free populations. It is well established that in addition to causing allergic disorders, IgE antibodies are the primary immune defense against parasites. The IgE response to parasites is both specific and non-specific, and thus results in highly elevated total serum IgE levels. Such polyclonal stimulation can diminish specific IgE antibody responses and cause saturation of mast cell receptors. As such, researchers hypothesize that, simplistically, IgE antibody produced in response to parasites saturates binding on mast cells that would otherwise be available for binding of IgE antibody produced from environmental allergens. As a result, parasite-infected individuals are less susceptible to developing hypersensitive immune response to allergens in the environment. These observations suggest that as dog owners become more efficient at eradicating parasites from their dogs, those dogs with a predisposition for elevated IgE production have a greater likelihood of developing symptoms of atopy. Researchers are currently exploring the therapeutic implications for certain parasitic components (proteins) to induce the IgE antibody saturation that occurs during infection with the whole organism. Such therapies may be beneficial for the management of atopy and other disorders resulting from immune hypersensitivity.

Symptoms: The most common symptom of atopy is "pruritis" (itching) usually beginning around the face and paws and which may eventually become more diffuse over other areas of the body particularly the ears, the armpits (axillae), the elbows, and the groin. Recurrent ear infections (otitis) are present in up to 75% of dogs diagnosed with atopy. Skin lesions are not usually apparent, unless resulting from excessive scratching, however, a raised, pustular rash with or without hair-loss may occur as a result of secondary skin infection (pyoderma). Some dogs may develop conjunctivitis.

Diagnosis: Because many other dermatologic disorders may present with similar symptoms to atopy, and because of the significant laboratory work-up required to diagnose the particular antigen(s) associated with the disease, certain criteria have been established to select symptomatic patients for further in vitro testing to identify the causative allergen:

1) member of a breed with a known predisposition for atopy
2) clinical symptoms manifesting between 6 months and 4 years of age
3) waxing and waning symptoms associated with seasonal changes
4) positive response to glucocorticoid treatment

Though waxing and waning symptoms during seasonal changes is the best indicator of atopy in a dog, a diagnosis of atopy should not be excluded in the absence of this observation since it has been found that up to 70% to 80% of dogs with atopy will demonstrate continual, year-round symptoms. When these criteria are met and other differential diagnoses are ruled out, then allergy testing to identify the responsible allergen(s) becomes the next consideration.

Principles of Allergy Testing. In general, though mixed allergen testing (combining antigens from different sources together) may be performed, since the purpose of testing is to identify a specific allergen or allergens for immunotherapy, testing each allergen individually is the preferred method. Common testing allergens include: grasses, trees, shrubs, weeds, molds, housedust mite bodies, mite eggs, mite larvae, mite feces, fleas, ants, flies, cockroaches, mosquitoes, moths, feathers, nylon, wool, silk, and tobacco. Food allergen testing is rarely effective for identifying food-related allergens; therefore, food elimination testing is the preferred method for screening for food allergies (to be discussed in the next series' article). Selection of allergens for the purpose of treating dogs with immunotherapy (hyposensitization treatment) may be done either through intradermal testing or in vitro testing. Each method has its strengths and weaknesses in terms of laboratory analysis. With intradermal testing, a commercially available antigen is selected and injected under the skin and the site of the injection is observed for signs and intensity of an allergic response. Many dermatologists utilize intradermal testing because it has a high level of specificity and thus positive results are more likely to be true-positives. The main limitation with this test is the occurrence of false-negatives because of poor sensitivity associated with this form of allergen testing.

An alternative to intradermal testing is the method of in vitro allergen testing. This second method requires reacting serum from the dog with a commercially-available antigen that has been bound to a solid substrate in a radioallergosorbent test (RAST) or enzyme-linked immunosorbent assay (ELISA) which measures the amount of IgE in the patient's serum that binds to the allergen. This test is particularly useful when evaluating dogs that have already undergone or are continuing treatment with glucocorticoids (since these drugs will inhibit intradermal test reactions yielding false-negative results). However, in vitro allergen testing has a higher degree of non-specificity and therefore, false-positive results. Recent modifications to methods of in vitro allergen testing by the Veterinary Allergy Reference Laboratory (VARL) have provided a means to increase the level of specificity of these in vitro tests aimed at detection of IgE through the use of monoclonal anti-IgE reagents. Additionally, this testing method also seems to provide comparable specificity while providing greater accuracy compared to intradermal testing for detecting insect-associated allergies.

Another limitation to in vitro allergen testing is that a subset of dogs with atopy has been found to have elevated levels of IgGd rather than IgE. As such, this group would fail to be identified by these previously described methods of testing which only quantitate IgE. To circumvent this limitation as well as to develop a more specific in vitro allergen test, another company, Heska, has developed an ELISA method using a high affinity Fc epsilon receptor alpha chain (Fce R1a ), which is the receptor involved in activating mast cells. This receptor binds only IgE and not other immunoglobins responsible for producing non-specific test results (though it may also bind IgGd which has been found to activate mast cells as well), and because it is the direct mechanism by which the allergic response is triggered, only immunoglobins involved in the allergic response would be quantitated for results. This particular strategy has resulted in increasing the accuracy of in vitro allergen testing to as high as 90% when compared to intradermal testing.

Treatment: Conventional therapy for atopy typically employs treatment with glucocorticoids for their anti-inflammatory benefits. However, systemic use of glucocorticoids is not looked upon favorably for long-term treatment of atopy, due to undesirable side-effects, and thus other therapeutic options have been clinically explored. Next to glucocorticoid treatment, immunotherapy (hyposensitization) has been found to be the most effective treatment for atopy and is effective either alone or in combination with other therapies (EFA and antihistamine treatment; discussed below) at completely circumventing the need for glucocorticoid therapy in as many as 75% of atopic cases. In some instances, immunotherapy alone may not be sufficient to control symptoms of atopy. Alternatives to resorting to glucocorticoids include antihistamines and dietary supplementation with essential fatty acids (EFAs), of which some have been found to have anti-inflammatory properties that have demonstrated efficacy in the management of atopy. Evening primrose oil has been evaluated in studies examining the benefits of EFA supplementation in dogs with atopy. As a result of clinical trials in this area, the following 5 observations have been made regarding supplementation with EFAs in the treatment of atopy:

1) EFA will not be effective in the face of significant inflammation, as occurs with secondary infections with bacteria or yeast.
2) EFA response is dose-related
3) The effect of EFA is associated with a lag period of at least 3 weeks. Maximal benefit may not be appreciated until after three months of treatment in some cases
4) Combining EFA with certain antihistamine treatments (chlorpheniramine, clemastine, or hydroxyzine) produces additive, and in some cases possibly synergistic (greater than additive) effects
5) Even if not able to alleviate systemic glucocorticoid therapy completely, EFAs can, in some cases, significantly reduce the dosage of glucocorticoids required to maintain therapeutic response

Commercially Available EFAs for Dogs
Efavet Regular capsules (Efamol Vet)
DermCaps or 3V Caps (DVM Pharmaceuticals)
EFA-Caps (Allerderm/Virbac)
Pet-Derm O.M. Caps (Smith-Kline Beecham)
Omega-3 Fatty Acid Capsules (Vet Solutions)

Principles of Immunotherapy. Immunotherapy (hyposensitization) is a therapeutic approach whereby an allergen is administered to a hypersensitive patient in an attempt to reduce allergic reaction when the patient is naturally exposed to the allergen in the environment. When a hypersensitive dog is administered an allergen, initially there is an increase in circulating IgE antibodies that later decreases. It is believed that the initial elevated level of IgE may 1) induce development of blocking antibodies; 2) induce suppressor T-cells; 3) induce the formation of anti-idiotype antibodies (antibodies directed against IgE antibodies); or decrease the susceptibility of mast cell to becoming activated. In any event, dogs receiving hyposensitization with specific allergens demonstrate reduced inflammatory reactions when later challenged by these same allergens, suggesting a positive effect for immunotherapy to control atopic disease.

Initially, immunotherapy begins with an induction phase whereby the dog receives an injection of the most dilute solution (1:100) of the standard concentration of allergen (typically 20,000 protein nitrogen units (PNU)/ml). Injections are administered every other day over an 8-day period while gradually increasing the volume of the diluted allergen (up to a maximum of 1 ml) during each injection. Beginning on day 10 following the first induction dose, the dog is administered a moderately concentrated dose (1:10 dilution) every other day over the next 8 day period, again, gradually increasing the volume with each injection as in the induction phase. Thereafter, a maintenance solution is administered every other day over another 8-day period, increasing volume with each dose as previously. Subsequent to this stage, intervals between treatments increase to 10 days, then eventually 20 days.

Effective maintenance dose and schedule must be modified according to the response of each individual dog. Some dogs may require higher maintenance doses to achieve optimum therapeutic response. In the case of seasonal allergies, dose may need to be increased during certain times of the year when environmental allergen exposure may be higher. Most dogs require consistent treatment to prevent recurrence of symptoms, however, in some rare cases, dogs may become permanently desensitized and thus, no longer require further therapy.

Though dogs may exhibit reactivity to more than one allergen in allergen screening studies, the highest therapeutic response rates are achieved when only 10 or fewer allergens are used for hyposensitization. Using more than 10 allergens at any one time for treatment may increase risks for severe allergic side-effects as well as have a diluting effect on each specific allergen, thereby minimizing success for treatment. Noticeable improvements resulting from immunotherapy may take as few as 2-1/2 to 3 months or up to 1 year. Though severe reactions (such as anaphylactic reactions) associated with immunotherapy rarely occur, mild to moderate side-effects such as exacerbation of atopic symptoms (pruritis), localized inflammation or tachycardia may require adjustment of dosage or in some cases necessitate discontinuation of treatment.

Prognosis: Response rates to immunotherapy for the treatment of atopy have been reported from 50% (partial response) to 100% (complete response) in individual dogs. On the average it is estimated that 60% to 70% of dogs treated with immunotherapy utilizing specific antigens, as determined by allergen screening, will have some degree of positive response to treatment. Simply using the most common allergens for immunotherapy in lieu of specific allergen testing, however, significantly decreases success of treatment to only 15% to 20% of cases. No significant difference in success rate for immunotherapy has been observed based upon method of allergen testing (intradermal testing or in vitro testing). Because of potential problems associated with allergen testing specificity described above, dogs that do not respond to immunotherapy to a particular antigen within one year of treatment are typically suspected of having had a false-positive screening or a differential diagnosis, thus necessitating the need for review of the initial diagnosis and possibly repeat allergen screening.

References:

Angarano DW, MacDonald JM. Immunotherapy in Canine Atopy. In Kirk's Current Veterinary Therapy XI, Bonagura, J.D. (ed.), W.B. Saunders Co., Philadelphia, 1992. pp. 505-508.

Boord, MJ, In vitro assays in the diagnosis and treatment of atopic disease. In Kirk's Current Veterinary Therapy XIII, Bonagura, J.D. (ed.), W.B. Saunders Co., Philadelphia, 1999. pp. 560-564.

Harvey, RG. Essential fatty acids. In Kirk's Current Veterinary Therapy XIII, Bonagura, J.D. (ed.), W.B. Saunders Co., Philadelphia, 1999. pp. 538-542.

Lynch NR, Hagel I, Perez M, Di Prisco MC, Lopez R, Alvarez N. Effect of anthelmintic treatment on the allergic reactivity of children in a tropical slum. J Allergy Clin Immunol. 1993 Sep;92(3):404-11.


 Copyright 2001. Pamela A. Davol. All rights reserved. Copyright & disclaimer.

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