Atopic Dermatitis: Causes, Signs and Treatment for Your Pet

Atopy is defined as an inherited predisposition to develop a type I hypersensitivity to environmental allergens. Historically, the allergens were presumed to be inhaled, but it is more likely that allergens are absorbed percutaneously and bound to epidermal Langerhans’ cells. Presentation of these allergens by the Langerhans’ cells to T cells leads to a preferential activation of Th2 cells that secrete cytokines favouring the production of allergen-specific IgE antibodies. These IgE antibodies are bound to the surface of circulating basophils and tissue mast cells. When allergens crosslink the surface-bound IgE antibodies, a degranulation of the cells with subsequent release of inflammatory mediators occurs.

Preformed mediators stored in the granules include histamine, heparin and proteolytic enzymes, but synthesis and release of other mediators such as prostaglandins and leukotrienes also occur at the time of degranulation. Erythema and pruritus, typical features of allergic disease, occur. Allergen specific IgGd antibodies have been implicated in the pathogenesis of atopic dermatitis, as they bind to mast cell surfaces, but their exact role in this disease is unclear. Strong breed predilections and limited breeding trials showed atopic dermatitis to be a genetically programmed disease. A further factor involved in the pathogenesis may include the magnitude of allergen exposure, particularly in puppyhood.

The term adverse food reaction encompasses immunological and non-immunological reactions to elements in the diet. The exact pathogenesis is currently unknown. For practical purposes it is useful to consider atopic dermatitis, adverse food reaction and flea allergy dermatitis as potentially co-existing problems.

According to the allergic threshold principle, pruritus from several concurrent skin diseases may ‘add up’. Every animal has an individual pruritic threshold below which clinical signs are not evident. In an animal with bacterial pyoderma secondary to atopy as well as concurrent flea bite hypersensitivity, some of the pruritus is caused by the pyoderma, some by the atopic dermatitis (AD) and some by flea bites. It may not be necessary to treat all the factors contributing to pruritus to reduce the level to below the threshold.

Management of flea allergy dermatitis and secondary pyoderma in a dog with atopic dermatitis may be sufficient to render the animal comfortable. Thus, it is of extreme importance for the management of atopic dermatitis to minimize the pruritus by addressing all the compounding concurrent or secondary pruritic skin diseases such as flea bite hypersensitivity, food intolerance, Malassezia dermatitis or bacterial pyoderma.

Clinical approach for Atopic Dermatitis

Atopic dermatitis is one of the most common skin diseases in the dog and the second most common hypersensitivity in the cat. Atopic dermatitis should be included in the differential diagnoses of any dog with pruritus or pyoderma and any cat with miliary dermatitis, eosinophilic granuloma, non-inflammatory alopecia or pruritus.

History

• The presenting complaint for most atopic dogs will be pruritus, although recurrent pyoderma completely responsive to antibiotics may also be due to atopic dermatitis. Owners often do not consider face rubbing or foot licking signs of pruritus and need to be questioned specifically about various forms of pruritus
• Clinical signs of canine atopic dermatitis begin typically during young adulthood, between 1 and 3 years of age, although atopic dermatitis may occasionally occur in animals as young as 3 months or as old as 12 years
• Initially, seasonal pruritus is most commonly reported, although this may vary with the climate and environment the patient lives in . However, owners commonly report an increasingly longer period of pruritus every year and after a few years many dogs are affected perennially
• Response to glucocorticoids at anti-inflammatory doses is seen in the vast majority of patients with atopic dermatitis without secondary infection. Glucocorticoids will decrease inflammation and pruritus in most patients initially, but a repeated good response indicates a high likelihood of allergic skin disease
• Certain dog breeds are predisposed to atopic dermatitis. These breed predispositions may vary from area to area (for example, German Shepherd Dogs are predisposed to atopic dermatitis in Europe and Australia, but not in the United States)
• Feline atopic dermatitis may affect cats of any breed or sex. Miliary dermatitis has been reported to occur more commonly in younger cats, but in general atopic disease may occur at any age in the cat

Physical examination

Symptoms of Atopic Dermatitis in Dogs

Salivary staining, alopecia, erythema, lichenification and erosions are seen on predilection sites; greasy and moist or scaly skin and otitis externa are commonly present. Unilateral otitis externa due to atopic dermatitis has been seen . Atopic rhinitis and conjunctivitis may occur concurrent to dermatological signs or individually. Acral lick dermatitis or pyotraumatic dermatitis (‘hot spots’) may also be due to atopic dermatitis. Clinical signs of secondary bacterial and/ or yeast infection, such as papules, pustules, epidermal collarettes and crusts , are commonly present.

Symptoms of Atopic Dermatitis in Cats

Atopy is a possible aetiology for a number of cutaneous reaction patterns. Miliary dermatitis, non-inflammatory alopecia and all lesions of the eosinophilic granuloma complex may be associated with feline atopic dermatitis. Feline atopic dermatitis may cause pruritic dermatitis with severe self-trauma, particularly of the head and neck, and subsequent alopecia, erosions, ulcers and crusting in more severe and chronic disease.

Differential diagnosis of Atopic Dermatitis

• Adverse food reaction
• Scabies
• Flea bite hypersensitivity
• Bacterial pyoderma
• Malassezia dermatitis
• cheyletiellosis
• Contact allergic or irritant dermatitis

Diagnosis of Atopic Dermatitis

The diagnosis of atopic dermatitis in small animals is usually based on history, physical examination and ruling out differential diagnoses. Willemse (1986) adapted major and minor criteria accepted for human atopic dermatitis for use in veterinary medicine. These criteria can be used as a guideline for the diagnosis of canine atopic dermatitis.

Allergy testing

Once atopic disease is diagnosed by history, clinical examination and ruling out relevant differential diagnoses, offending allergens may be identified with either intradermal testing or serum testing for allergen-specific IgE. Decreasing allergen exposure may be achieved in some patients, although typically only with limited benefits. Animals with increased pruritus during or directly after walks are more likely to be allergic to pollens. If the pruritus is predominantly present indoors, house dust mites are more likely.

Thus, the predominant purpose for allergy testing is to allow the formulation of a patient-specific allergen extract used for immunotherapy or allergy shots. Implications, costs, adverse effects and prognosis need to be discussed in great detail with the owner before considering any form of allergy testing. At present, intradermal testing is considered the test of choice for the identification of allergens involved in atopic dermatitis by most dermatologists, serum testing for allergen-specific IgE is accepted as a second-best solution.

(1) Intradermal testing: In preparation for intradermal testing , it is important to observe the withdrawal times for various anti-inflammatory drugs that may interfere with skin test reactivity. Animals are sedated and placed in lateral recumbency, an area on the lateral chest is clipped and a number of allergens, a negative control (typically saline solution) and a positive control (typically histamine), are injected intradermally. Relevant allergens will bind to allergen-specific IgE on the surface of intradermal mast cells, cross-link these receptors and lead to mast cell degranulation and formation of an erythematous wheal. After 15-25 minutes the reactions are evaluated and compared to the negative and positive control. Based on their diameter, induration and erythema, a score from 0 to 4 is assigned (0 being determined by the negative, 4 by the positive control). The severity of the reactions does not necessarily correlate with the severity of the clinical signs.

Negative intradermal tests in atopic patients may occur for several reasons : 

• Although selection of allergens for skin testing aims at choosing the most relevant allergens for the local environment and thus identifies the vast majority of atopic patients, it is limited by availability of allergens, lack of knowledge about dog- and cat-specific allergens and financial constraints. Thus, the patient may be allergic to allergens not included in the test
• Withdrawal periods for anti-inflammatory agents may not have been observed or may have been too short for the particular patient
• Due to constant exposure to certain allergens and subsequent constant degranulation of mast cells, there may not be enough intact, ‘loaded’ mast cells present to cause a strong wheal and flare reaction to these allergens in the height of the allergy season. The ideal time for intradermal testing in atopic patients with seasonal clinical signs is shortly after the end of the allergy season for that particular patient
• Some atopic patients consistently lack positive reactions on skin testing and will show positive reactions on serum testing for allergen-specific antibodies. The reason for this is not currently known
• Severe stress theoretically may cause release of sufficient endogenous glucocorticoids to inhibit skin test reactions

‘False-positive’ skin test reactions are less common and may occur due to cross-reactivity of allergens. An example is the reported cross-reactivity of housedust mites with scabies antigen, leading to false-positive reactions against dust mite antigen jn dogs with scabies. Subclinical atopic dermatitis may cause positive reactions on skin tests of clinically normal dogs, which may be under their pruritic threshold at the time of testing. Irritant or true false-positive reactions may also occur. Carefully ruling out differential diagnoses for atopic dermatitis and thus skin testing of clinically atopic patients is the best assurance against falsepositive skin test reactions.

(2) Serum testing: Various companies around the world offer serum testing for allergen-specific IgE. Enzyme linked immunosorbent assays (ELISA) and radioallergosorbent tests (RAST) are offered; the results of ELISA tests seem to be more reproducible. With newer technology and tests based on monoclonal anti-lgE antibodies, the false-positive reactions so commonly seen some years ago have become fewer. Tests evaluate either individual allergens or grouped allergens (e.g. several individual grass pollens in one group). The vets do not recommend results of the latter as a base for formulation of allergen-specific immunotherapy, as allergens not involved in the patient’s disease may be included in the vaccine and potentially lead to new allergies in this particular patient. 

Negative serum test results in atopic patients may occur due to allergen selection or inherent patient factors. Interference of anti-inflammatory drugs, particularly glucocorticoids, varies depending on the serum test used. Some tests are extremely sensitive and will not show positive reactions after glucocorticoid therapy, others seem to be less influenced by it. Negative results due to drug interference seem to be more common in patients on long-term therapy with glucocorticoids even at low doses.

lucocorticoids even at low doses. ‘False-positive’ results will be due to either subclinical atopic dermatitis, inherent problems of the assay or cross reactivity of allergens and seem to be more common than in skin testing.

It is even more important to perform a meticulous diagnostic work-up prior to serum testing than prior to intradermal testing.

Management and Treatment of Atopic Dermatitis

The client has two major options. In patients with atopic dermatitis, the disease may be further characterized by identifying offending allergens with intradermal testing or serum testing for allergen-specific IgE. This allows formulation of allergen-specific immunotherapy, currently the only treatment modality specific for atopic disease. It also occasionally may provide clues for limiting the exposure to involved allergens. The other option is symptomatic anti-pruritic therapy without specific knowledge of allergens involved in the disease.

In patients with adverse food reaction, a sequential rechallenge with individual proteins, as described above, will often identify the offending food ingredient(s), which then need to be avoided. An alternative is to continue long term with a commercial diet that is well tolerated by that particular patient without determining which ingredient of the original food was responsible for the clinical signs.

Allergen-specific immunotherapy (allergy shots)

Hyposensitization (also called desensitization or allergy vaccination) involves subcutaneous injection of relevant allergens at intervals and in increasing concentrations (induction period), until the target maintenance dose is reached. This dose is administered on a regular basis as needed by the patient. The success rate of this therapy varies between 50% and 80% in most studies. Improvement is not expected for the first few months of therapy. Allergy shots must be given for at least one year before determining if the treatment is ineffective and should be stopped.

Symptomatic Systemic Treatment

Most dogs and cats will receive glucocorticoids, antihistamines, fatty acid supplementations or a combination thereof. In refractory patients, newer and/or more expensive drugs may be considered.

(a) Glucocorticoids: At anti-inflammatory doses, glucocorticoids are the most effective drugs for atopic dermatitis; the dose used in cats is usually higher than that in dogs. Prednisone and prednisolone are most commonly used. Some animals may not respond well to these treatments or may experience significant side effects like excessive urination (PU), excessive drinking (PD), or increased appetite (polyphagia), and might benefit from alternative medications.

Alternate-day or every third day therapy is generally preferred over daily administration; however, some dogs respond better to a low daily dose of glucocorticoid rather than a higher dose given on alternate days. Atopic patients on glucocorticoid therapy may initially respond well to low doses, but their response may diminish over time. Adverse effects of glucocorticoid therapy are listed in Figure18.17. Severe calcinosis cutis has been seen in dogs on 0.2 mg/kg of prednisone every other day for a few weeks to months. Although this is not common, it emphasizes that there is no ‘safe’ dose of glucocorticoids. Oral administration is preferred because it allows for quicker and easier dose adjustments.

A sparing effect of antihistamines and fatty acid supplementations has been reported in various studies, even in patients where these antihistamines and fatty acids had not improved the condition at all on their own. Gradually reducing the glucocorticoid dose to the minimum needed to control pruritus, followed by the addition of antihistamines or fatty acids, can often significantly lower the glucocorticoid requirement and is always recommended.

The Veterinarians routinely treat atopic dogs with fixed doses of antihistamines and fatty acid supplementations at the same time and add just as much of the glucocorticoids as is needed at that particular time. If the patient shows no sign of pruritus, the dose of the glucocorticoid is decreased until mild pruritus is present. This approach enables the dose to be adjusted to the minimum needed for each individual patient, as their requirements may vary from week to week and change with the seasons.

(b) Antihistamines: Antihistamines are used more and more commonly in the treatment of atopic dermatitis because of their safety. Their success rate in dogs is relatively low, with only an estimated 30% of atopic patients responding completely. Cats respond much better: the success rate is up to 70%. An antihistamine trial is recommended for any cat to which owners are able to administer tablets on a daily basis. As the lack of response to one antihistamine does not rule out a good response to another, patients will routinely undergo an antihistamine trial where several different antihistamines are administered one at a time for about 10-14 days. Typically, low-priced antihistamines are used first. Although sedation is seen commonly in humans, this adverse effect is not as common in small , animals. Even if there is a mild sedation during the first 3-4 days, this often resolves within the first week of treatment. Two antihistamines given concurrently at their normal doses may be more effective in decreasing a patient’s pruritus and a variety of combinations are used in veterinary dermatology. Giving two antihistamines concurrently does not seem to result in a significantly higher incidence of adverse effects. Only antihistamines of different classes should be administered concurrently. Antihistamines are also commonly combined with essential fatty acid supplementation. Due to their glucocorticoid-sparing activity, antihistamines are commonly used in dogs as adjunctive therapy, even if their efficacy as a sole treatment is not satisfactory. 

(c) Essential fatty acid supplementation: EFA supplementation causes an alteration of the composition and function of the epidermal lipid barrier and attempts to switch the production of inflammatory mediators such as prostaglandin E2 or leukotriene 84 to less inflammatory or non-inflammatory prostaglandins and leukotrienes. The success of this competitive inhibition varies. Complete resolution of pruritus is seen in a minority of atopic dogs only. In atopic cats, the success rate with fatty acid therapy is higher and may approach 50-70%. Dry and scaly skin in atopic patients is more likely than pruritus to respond to fatty acid supplementation. 

Essential fatty acids are also known for their glucocorticoid-sparing activity and are used frequently as adjunctive therapy in combination with these and/or antihistamines and allergen-specific immunotherapy. Various products are available. They are based either on omega-3 fatty acids (such as eicosapentaenoic acid in marine fish oil), omega-6 fatty acids (such as linolic acid in sunflower or safflower oil or ,(linolenic acid in evening primrose oil) or a combination thereof. A number of studies have evaluated the success rate of various fatty acid supplementations at various doses. At present, no clear guidelines can be given as to which type or ratio of omega-3:omega-6 fatty acid supplementation is most suited for the treatment of atopic dermatitis, although the some vets prefer omega-3 fatty acids or a combination of omega-3 and omega-6 fatty acids for the treatment of pruritus. Products based on omega6 fatty acids may be more suitable for the treatment of dry skin and secondary seborrhoea sicca associated with atopic dermatitis. 

Approximately 50 mg/kg daily or more of eicosapentaenoic acid or linoleic acid are administered. The required dose may vary depending on the fatty acid content of the atopic patient’s diet. In general, higher doses will give better response rates but also increase the risk of diarrhoea, the most common adverse effect of fatty acid therapy. Occasionally, pancreatitis and (with fish oil-based omega-3fatty acids) bad breath are noted. The caloric density of these supplements necessitates a reduction in food intake to keep the body weight constant, particularly at higher doses.

If administering capsules to the patient is a problem, capsules can be pierced and the fatty acids mixed in with a small amount of food. Omega-3 fatty acids typically smell and taste very fishy and pets disliking fish will not eat this mixture, while animals favouring fish will be more inclined to eat it. Omega-6 fatty acids have a less intense odour and taste and may be given in food more easily. Although some controversy exists about the time ·period of fatty acid supplementation before effects can be evaluated, they should be administered for a minimum of 8-10 weeks, based on fatty acid concentration changes in serum and skin with supplementation.

(d) Ciclosporin: Another drug receiving attention in human and veterinary medicine is ciclosporin. It is an inhibitor of IL-2 production, and thus T-cell activation, and is very effective in many patients with atopic dermatitis. Ciclosporin is given at 5 mg/kg daily. It is metabolized in the liver. Drugs metabolized by the same enzyme system, such as ketoconazole, prolong its half-life and have been used to decrease the dose requirement of ciclosporin for financial reasons in some countries. The ciclosporin dose may be decreased by 40-90% with concurrent ketoconazole administration at 5-10 mg/kg twice daily.

Adverse effects seen include vomiting and diarrhoea. As yet, hypertension and kidney failure seen in humans have not been a problem in dogs. At doses of 15 mg/kg daily and higher given to transplant patients or patients with immune-mediated skin disease, gingival hyperplasia, weight loss, lameness, increased hair and claw growth have been reported. The long-term side effects of this form of therapy in the dog are not known. In atopic patients successfully controlled with ciclosporin, decreasing the dose below 5 mg/kg frequently leads to recurrence of clinical signs. However, the frequency of administration may be decreased to alternate days or twice weekly in some patients. This is a topic of ongoing investigation.

(e) Pentoxifylline: Pentoxifylline has also been administered to dogs with atopic dermatitis at 10-15 mg/kg bid or TID. Although improvement of some clinical parameters has occurred in clinical studies, pruritus did not improve significantly compared with the placebo group. Pentoxifylline may have a place as an adjunctive therapy in dogs with mild to moderate disease.

(f) Misoprostol: Misoprostol, a prostaglandin E2 analogue has also been evaluated as a potential treatment for canine atopic dermatitis at a dose of 6 micrograms/ kg tid. As a sole antipruritic agent it does not perform well but it is effective in some individuals in combination with antihistamines and/or topical therapy.

(g) Psychotropic agents: In animals refractory to treatment with the above outlined treatments, psychotropic agents such as amitriptyline at a dose of 1-2 mg/kg bid or fluoxetine at a dose of 1 mg/kg sid may be used. Adverse effects include all those seen with antihistamines but psychotropic agents may also result in abnormal and strange behaviour, lower the seizure threshold and induce cardiac arrhythmias.

Topical Treatment for Atopic Dermatitis

Topical therapy may also be of benefit to many patients with atopic dermatitis. A number of antipruritic shampoos are available.

(a) Demulcents and moisturizers: These are common ingredients of shampoos. A demulcent is a highmolecular-weight compound in aqueous solution which coats the skin surface, thus protecting the underlying cells and alleviating irritation. Urea promotes hydration and is antibacterial. Glycerine is a popular vehicle and a hygroscopic agent which is absorbed into the skin. Linoleic acid is very important for the barrier function of the stratum corneum, particularly affecting transepidermal water loss. Topical application of fatty acids has been shown to influence epidermal fatty acid levels and may help hydrate the stratum corneum by decreasing trans-epidermal water loss. Colloidal oatmeal hydrates the stratum corneum by attracting and binding water as it moves through the epidermis, acting as a hygroscopic agent.

(b) Anti-inflammatory ingredients: Hydrocortisone, antihistamines and Aloe vera extracts have been incorporated into shampoos. Antihistamines and hydrocortisone are believed to penetrate the epidermis and provide antihistaminic and anti-inflammatory effects within the upper dermis. The prolonged use of hydrocortisone in shampoo form has demonstrated clinically negligible systemic absorption. Anti-inflammatory properties of aloe vera have been reported in rats based on inhibition of cyclo-oxygenase activity and neutrophil migration. In some patients, topical therapy alleviates pruritus for several days and owners may choose to continue weekly or twice weekly shampoo therapy. Other patients do not benefit from topical therapy enough to consider this form of treatment for long-term management. 

(c) Anti-infective ingredients: Frequent use of shampoos containing antibacterial and antifungal agents such as chlorhexid ine, benzoyl peroxide and miconazole is often beneficial in the management of those dogs with a particular predisposition to bacterial and yeast infections.

Conclusion

In conclusion, there is no single uniformly effective therapeutic agent or management approach for canine or feline atopic dermatitis, and the succesful remedy is usually a combination of topical treatments, systemic therapeutics and environmental changes. The management of atopic patients is frequently a challenge requiring a dedicated and educated client willing to put in significant personal, emotional and financial effort, and a veterinary surgeon willing to invest a significant amount of time to guide and advise the client long term in the search for the best therapeutic approach for that particular patient. However, this is an area of intense research in both the human and veterinary field, and it is likely that newer and more effective therapies will become available within the next decade.