Long Term Management of Canine Atopic Dermatitis
Didier-No�l Carlotti France
The criteria set out by T. Willemse (1986) have been unanimously accepted to establish the diagnosis of canine atopic dermatitis (AD). A revision has been proposed by Pr�laud in 1998. As emphasized by C. Griffin (1993), the demonstration of in vivo or in vitro sensitization, is, for many dermatologists, an important criterion for the diagnosis and treatment of AD. This is not the case for man, but if the two diseases have common points, they are not identical.
Treatment of DERMATOSES THAT are related or secondary to atopic dermatitis
According to the phenomenon of summation of effects, several causes of pruritus (allergic and non-allergic) may simultaneously arise in the same animal with a variety of clinical presentations and cause it to rise above its pruritic threshold. Secondary pyoderma is common in canine AD and an adequate treatment regimen may return the animal to a quasi-normal state. Such a case will only be treated in cases of regular reoccurrence and/or if the atopic dermatitis clinical signs become a concern. This reasoning is undoubtedly applicable as well to cases of Malassezia dermatitis. One third of atopic dogs will become sensitive to fleabites in their life and develop flea allergy dermatitis (FAD) and four out of five dogs suffering from FAD are atopic. A well-conducted flea control regimen can eliminate the FAD, and therefore, in certain cases, can enable the animal to fall under its pruritic (i.e., tolerance of pruritic causes) threshold. In such a case, atopic dermatitis treatment is not necessary if the clinical signs are not obvious. If this not the case, the atopic dermatitis should be treated while maintaining absolute antiparasitic treatment. Food intolerance may resemble AD and a food elimination diet is relatively easy to perform.
Allergenic eviction is �theoretically� the ideal treatment for all cases of allergic dermatitis. Totally avoiding the allergen may enable the animal to fall beneath its pruritic threshold, identical in this instance to the allergic threshold. This avoidance is illusive in the case of pollens. However, it is possible to eliminate environmental feathers and fabrics, and molds can be destroyed by antiseptic or antifungal sprays or even anti-mold paint. However, the role of these allergens in dogs' atopic dermatitis is minimal, and moreover, feathers and fabrics are mostly sources of house dust mite allergen.
Various methods exist to fight against house dust mites, and if necessary, these may be tried around atopic dogs: elimination of furnishing fabrics, carpets, curtains, cushions, etc.; frequent vacuuming with a High Efficiency Particle Air (HEPA) filter vacuum cleaner, which will not release mite particles into the air; use of air dehydration and purification devices; use of acaricide sprays and foggers (some of which contain an Insect Growth Regulator (IGR) and a denaturing agent such as tannic acid which is very efficient for both mite faeces and fungal spores); use of anti-mite mural paints (also anti-insect and anti-mold); use of cushions and covers that can be washed at high temperatures as beds for dogs; and use of protective covers produced for asthmatics (e.g., made of teflon, though these are expensive). An atopic dog which is sensitive to cat dander could, in theory, benefit from cat major allergen avoidance measures (Fel d I) although this allergen is not proven to be recognised by the atopic dog. Because this allergen is transported through the air, it is imperative to take measures against it even if there is no cat living in the house. The measures to be taken are similar to those against mites and also aim at reducing the Fel d I level in cats, which is present in the sebum and is favoured by testosterone secretion, through male castration and frequent baths or shampoos.
These general measures could therefore be used for atopic dogs and are especially advised if many of them are involved. However, no scientific study has formally proven their usefulness in canine atopic dermatitis.
Hyposensitisation (immunotherapy, desensitisation) has been used in humans, since the beginning of the 20th century, to treat asthma and allergic rhinitis but never in dermatology (although it is also used in cases of hypersensitivity to hymenoptera bites). It first was reported in dogs in the 40s, expanded in North America in the 60s and in Europe in the 1980s. The first explanation for desensitisation efficacy in man was in the production of blocking antibodies (lgG), which combine with allergens before they combine with the IgE. Today, many mechanisms are proposed. In brief, the intervention of other anti IgE anti-bodies (IgG anti IgE, anti-idiotype anti-bodies) has been proposed as well as allergen-specific IgG immune complex, which regulate the immune response. In the same way, acting on Th2-Th1 substitution will lead to a reduction in the IL4 production and an increase in the INF-gamma production. The IL4 offers potential for the IgE synthesis, increases the number of weak affinity IgE receptors or their CD23 soluble form. The INF-gamma inhibits IgE synthesis. Late phase reaction inhibition in desensitized subjects is accompanied by the apparition of T-lymphocytes with a Th1 profile. Finally, desensitization may be accompanied by a cellular and tissue hyposensitisation by reducing the basophilic reactivity, blocking the eosinophilic migration, reducing the neutrophils� chemotactic activity and abolishing the cytotoxic activity of platelets, among others. These mechanisms can sequentially intervene and differ between the induction and maintenance phases. Halliwell reports IgG and IgE variations in dogs, in both directions, over a two-year period without any clinical correlation. It is reasonable to think that the blocking anti-bodies hypothesis is only a simplification and that no single mechanism can explain the dog's immunotherapy efficacy.
The choice of allergens mainly depends on the in vivo or in vitro test results. Skin tests represent the reference to identify the responsible allergens if they are correctly carried out. The use of biologically standardised allergens, even using human allergy techniques, is preferred. The EIA techniques' serological diagnosis is attractive due to its simplicity. There is a controversy about the reproducibility, and the sensitivity is considered as either weak or very high, but therefore, having a low positive predictive value, which renders the test void. The polyclonal antibodies can have superior values, but if many monoclonal anti-bodies are used grouped, good results can be achieved. Recently, an innovative technique using human specific IgE receptors (FceR1�) has been proposed. The cellular tests (basophils degranulation test, heterologue passive transfer test) are expensive and require specialized laboratories.
Test results are to be interpreted taking into account the history of the patient and the clinical presentation. Therefore, it must be logical to include allergens in a desensitization protocol (in the case of a positive reaction, danders, molds, pollens, etc., are only used if they are present in the environment). This principle must however be nuanced in the case of cat dander. No standardisation exists for the methods used. Only aqueous extracts are used in North America, whereas in Europe, mainly alum-precipitated extracts are available. It seems that the combination of molds and pollen extracts alters their quality (due to the presence of protease in the mold extracts) and that different types of vials are necessary.
Desensitization is efficient in man as testified in the results obtained in allergic rhinitis. The hyposensitization results are more or less difficult to evaluate in dogs. In fact, they depend on the animals (age and especially diagnostic criteria), evaluation criteria (telephone follow-up, clinical score), follow-up duration, and recognition or not of �loss of follow-up� as setbacks. Presently, it is considered that 50 to 80% of animals respond to immunotherapy in open studies. T. Willemse demonstrated in 1984, the method's efficacy through a double blind controlled study. The nine-month evaluation seems important: it is usual that improvement at this stage is followed by success.
What are the result variation factors (apart from the diagnostic value and the clinical criteria of each one)?
Allergen identification method:� the combination of in vivo and in vitro tests increased success rates, even if it is impossible to confirm the same success rates in the in vitro tests as those obtained after skin-tests.
Allergen specificity: Willemse demonstrated that specific desensitization (based on skin-test results) is significantly more efficient than standard desensitisation (domestic dust, dog and human danders and grass pollens). Kristensen (1994) had better results with specific desensitization in dogs sensitive to Dermatophagoides farinae and/or D. pteronyssinus than with allergens' incorrect choice.
Allergen nature: Mueller et Bettenay (1996) showed that results were clearly better in dogs sensitive to pollens or Dermatophagoides farinae and pteronyssinus mites than in patients sensitive to molds or insects.
Number of allergens: it does not seem to have any influence.
Breed: no correlation exists between breed predisposition and results. English Setters seem to respond well as opposed to Boxers and West Highland White Terriers.
Age: results are better in the young animal and when the desensitization is carried out at an early stage.
Patient follow-up: Rosser showed in 1996 that results are better in dogs that are closely followed, adapting the injection dosage and frequency according to the tolerance and efficiency.
The use of highly purified allergens could improve results knowing that dogs are becoming sensitized to allergens other than those causing hypersensibility to Dermatophagoides farinae (Der f I and Der f II) and D. pteronyssinus (Der p I and Der p II) in the case of humans. No study has yet proven that the use of corticosteroids during desensitisation would have a very harmful effect on its efficacy. Antibiotic therapy and use of anti-seborrhoeic shampoos do not improve results. Rare cases of secondary effects have been mentioned in an anecdotal manner (urticaria, angiodema, anaphylaxis). An exacerbation of clinical signs is often noticed in the hours following injections. Limited local reactions, which are spontaneously reversible, often appear with alum-precipitated extracts. A majority of veterinary dermatologists believe the efficacy and absence of secondary effects justifies ad vitam eternam hyposensitization. They have empirically noted that the clinical signs reappear in a period of months to years after the treatment has been stopped.
This is useful at the beginning of hyposensitisation (within the first year in successful cases) or on a long-term basis in failed cases (total or partial), or even in cases where treatment was not required (aged animal, owner's hesitation or even, clinically slightly worrying cases apart from a few signs).
Corticosteroids are the most effective medications amongst the symptomatic treatment of allergic dermatitis. They have a powerful anti-inflammatory and anti-pruritic activity. They act at almost all inflammatory and immunological response stages. Their activity, however, varies tremendously. There is no consistency in the individual reaction, not only in relation to the corticosteroid used, but also for the same corticosteroid. The effect is reduced over time and the doses required are increased. They are used topically or systemically. Topical application is of limited value because of the hair (except perhaps as shampoos). Systemic therapy should be limited to the oral administration of prednisolone or methyl-prednisolone (0.5 to 1 mg/kg/day during five to seven days followed by 1 mg/kg every other day, as shortly as possible). Systemic corticosteroids have significant side effects. The most common are polyuria-polydipsia, polyphagia, hepatomegaly, hypothalamo-hypophyso-adrenal axis inhibition, drying of the skin and coat, and alopecia� (iatrogenic Cushing�s disease, which is often due to repeated injections of long-acting formulations). Local immunosuppression may give rise to infections (pyoderma), demodicosis, and dermatophytosis. The following rules must be respected regarding the long-term side effects of corticosteroids: use them as little as possible and use the lowest dose possible, preferably every other day and only if alternative anti-pruritic medications have been deemed inefficient.
Various non-steroidal topicals can be used. Anti-seborrhenic shampoos and rehydrating sprays may be used. Some of these contain oatmeal colloidal extracts with an antipruritic action. Recently, a shampoo containing linoleic acid, mono-oligosaccharids, vitamin E (immunomodulatory effects), and piroctone olamine (antiseptic) has been available. Essential fatty acids could reinforce the lipidic barrier role of the epidermis, which is altered in the atopic dog. Due to the probable skin penetration of allergens, a mechanical allergenic elimination effect would therefore be beneficial. Some local use sprays (e.g., containing menthol and hamamelis extracts) may soothe erythematous and excoriated areas. A lotion containing mono-oligo saccharides, vitamin E, linoleic acid, and chitosanide has been put on the market in conjunction with the aforementioned shampoo. Rinses containing pramoxin, a local anaesthetic, could also be helpful.
Some antihistamines that block H1 receptors may be useful; antiH2 are ineffective. Many studies have been performed showing that the most efficient products are clemastine, chlorpheniramine, hydroxyzine, oxatomide and diphenhydramine with approximately 20 to 30% beneficial results. However, only one placebo-controlled, double blind study has been carried out, using astemizole, clemastine and trimeprazine. Moreover, some frequently used products such as cetirizine or ketotifene have not been evaluated at all. Oxatomide also blocks intracellular calcium transport with ketotifene and rupatidine equally blocking other mediators. The relatively low success rates justify successive tests during at least one week at a time, until a satisfactory result is obtained. Trimeprazine, which alone is inefficient, has proven to be able to clearly reduce the need for prednisone. Three studies clearly show a synergic effect between the essential fatty acids and antihistamines. It is therefore possible to control cases having this type of association although they do not respond to any of these treatments.
Essential fatty acids (EFA) have been the subject of many clinical studies. The fatty acids that have been studied are polyunsaturated, administered by oral route, especially omega-3 series eicosapentanoic acid (EPA), and omega-6 series gamma linolenic acid (GLA). These fatty acids compete with the arachidonic acid in the cascade of eicosanoids synthesis where leukotrienes and prostaglandins are formed having an anti-inflammatory activity or at least a pro-inflammatory activity which is much less significant than that observed with the metabolites emitted from arachidonic acid. Various studies have proven their efficacy, including two double blind placebo controlled studies. However, various elements have not yet been made clear: dosage (varying from two to 10 times the advised doses), optimal ratio between omega-3 and omega-6 (between five and 10), the minimal duration of the therapeutic test to predict efficacy (one to 12 weeks), the function of co-factors, the usual diet and its essential fatty acid content, as well as associated therapeutics. The reaction of atopic dogs to fatty acids varies and no supplement or ration exists which suits all dogs; thus, several formulations should be tried, as is done for antihistamines. There are few side effects with EFA (bad breath, diarrhea, with high doses). In practice, they are to be principally used with other anti-pruritic treatments. A dietary approach, based on the quantity of omega-3 and the ratio omega-3/omega-6 may be helpful.
Leukotriene inhibitors have been tried in a few clinical trials. Zileuton, for instance, was not very effective in a placebo-controlled study. Phosphodiesterase inhibitors have shown a moderate efficacy in comparative (arophylline) or double blind, placebo-controlled crossover (pentoxyfilline) studies. Fluoxetine, an anti-depressive agent which inhibits serotonin uptake, and amitriptyline, a tricyclic anti-depressive agent with a antiH1 activity, appears to be moderately efficacious giving good results comparable to the �best� antihistamines (20 to 30 %). Misoprostol, a prostaglandin E analog, has shown interesting effects, including within a blinded placebo controlled study. Cyclosporine is a promising drug for the treatment of canine AD, as in man (administered orally). No significant difference was found in a recent comparative study vs. prednisolone. An injectable formulation of fatty acid copolymers has been shown to be more effective than a combination of antihistamines in a blinded comparative study. Some atopic dogs have bacterial overgrowth and respond to thorough antibiotic treatment regimen, even without visible signs of secondary pyoderma.
Conclusion: combination therapy case management
Each case is different and deserves a �combination therapy,� which associates treatment of complications, eventual allergen eviction measures, symptomatic therapy, and hyposensitisation. It is the key to success.
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