Atopic Dermatitis

Description

Atopic dermatitis is a heritable disorder in which animals are hypersenstive to common environmental allergens. It is one of the most common skin diseases of dogs worldwide.

The most common allergens involved in atopic dermatitis are those of house dust mites (Dermatophagoides farinae) and grain mites. Human and animal danders, house dust, grass and tree pollen and moulds also frequently incite reactions. Susceptible animals produce allergen-specific IgE to these normally-innocuous allergens, which then binds to receptors on cutaneous mast cells. Atopic animals may have defects in the epidermis, leading to impaired barrier function, and it is thought that further allergen exposure occures via percutaneous absorption. This further exposure gives mast cell degranluation, releasing istamine, cytokines, chemokines, leukotrienes, prostaglandins and other chemical mediators. This is a type 1 (immediate) hypersensitivity reaction¹, and leads to vasodilation, inflammatory cell infiltration and pruritus. It appears that the cytokines involved are abnormally biased towards a Th2 response. IL-4 in particular is produced; this cytokine is responsible for B-cell production of IgE. Bacterial superantigens and autoantigens released due to keratinocyte damage play a role in perpetuating inflammation.

Signalment

Atopic dermatitis is a disease of dogs, although it can occur sporadically in the cat¹. The typical age of onset of atopic dermatitis is between 6 months and 3 years of age and signs are hardly ever seen in animals under 6 months of age. Signs may be so mild at first thtat they are not noted, but usually progress to become clinically apparent¹. Atopy is heritable and so breed predispoitions occur. Susceptible breeds include the : Beaceron, Boston Terrier, Boxer, Cairn Terrier, Cocker Spaniel, Dalmation, English Bulldog, English Setter, Fox Terrier, Sealyham Terrier, Setters, Shar-Pei, West Highland White Terrier, Wire Hiared fox Terrier, and Yorkshire Terrier². Certain breeds such as the Cocker Spaniel, Dachshund, Doberman Pinscher, German Shepherd, German Short-haired Pointer and Poodle appear to have a decreased risk of atopy. There is no sex predilection.

Diagnosis

The diagnosis of atopic dermatitis is based on the signalment, athorough history and appropriate physical examination findings. Other causes of pruritus must also be ruled out. The differential diagnoses are¹:

• Food allergy: ruled out by a dietary exclusion trial.
• Flea allergy dermatitis: ruled out observing response to ectoparasiticides.
• Contact dermatitis: ruled out by confining animal to one area covered in e.g. newspaper.
• Scabies:ruled out observing response to ectoparasiticides.

Intradermal and serologic allergy testing are available but are not used to make a diagnosis of atopy. Their purpose is to identify the specific offending allergens in an animal in order than immunotherapy may be pursued. The results of allergy testing are only significant if the history and clinical signs are also suggestive of atopic dermatitis.

Clinical Signs

Signs are often, but not always, seasonal. Pruritus is the hallmark of atopic dermatitis and may be the only complaint. This gives rise to self-trauma, causing lesions. Lesions commonly include alopecia, erythema, scaling, crusting, excoriations and salivary staining. Macular-papular eruptions are occasionally seen². With time, lichenification, and hyperpigmentation develops. Because the route of allergen contact is thought to be percutaneous absorption^{1, 2}, it follows that hairless regions are most frequently affected: the face, ears, axillae, feet and inguinal regions are predilection sites. Secondary infections such as superficial staphylococcal pyoderma and Malassezia are common, and otitis externa often occurs concurrently^{2, 3, 4}. A small number of cases exhibit only chronic or recurrent otitis externa. Another uncommon presentation is allergic rhinitis, manifesting as sneezing, nasal discharge or allergic conjunctivitis^{1, 2}.

Laboratory Tests

Routine haematology and biochemistry rarely show any abnormalities in dogs, but eosinophilia is often seen in cats¹. The measurement of total serum IgE levels is not useful in the diagnosis of atopic dermatitis as IgE levels do not significantly differ betweem atopic and normal animals². IgE levels are also influence by the presence of parasites, vaccinations and breed, and so this test is not reliable

Allergen-specific IgE tests are only useful when a diagnosis of atopic dermatitis has already been reached by consideration of histoty and clinical exam, and by ruling out other causes of pruritus. The test is used to identify allergens for immunotherapy by evaluating serum levels of IgE specific for a variety allergens. The exact technique varies between laboratories, but the principle is the same: serum is allowed to react with the allergen before excess serum and antibodies are rinsed away. An IgE-specific reagent linked to an indicator is added, and the amount that binds is proportional to the amount of allergen-sprecific IgE². This can then be quantified. Several factors can adversely influence the test results. These include age, season, use of corticosteroids and laboratory inaccuracies.

Other Tests

Intradermal skin tests determine the ability of allergens injected intradermally to cause mast cell degranulation leading to a subsequent wheal and flare reaction. It is therefore a close approximation of the pathogenesis of atopic dermatitis, and is a useful tests for revealing specific allergens for use in immunotherapy. Aqueous allergens are used for testing and include such things as house dust mites, pollens, moulds, insects and epidermal antigens. These should be stored in the fridge to maintain potency, and allowed to reach room temperature before testing². Test results can be affected or inhibited by numerous factors such as medications, sedatives and stress. Drugs shown to affect intradermal skin testing include antihistamines, tricyclic antidepressants and glucocorticoids. Withdrawal times of 2, 4 and 8 weeks have been suggested for topical, oral and long-acting injectable steroids respectively, although this may be diffcult in a very pruritic animal. Some animals require sedation for intradermal skin testing and xylazine and medetomidine have been shown not to affect results. Diazepam and acepromzine should not be used².

26-27 gauge needles are used to inject allergen intradermally. Histamine is used as a positive control, and isotonic saline as a negative. Approximately 0.05-1.0 ml solution is injected at each site, and after around 15 minues the test is read by scoring each allergen based on the size of the bleb.

Biopsy

Biopsies may help rule out other differential diagnoses, but do not show any pathognomic changes for atopic dermatitis¹.

Pathology

Gross findings reflect the lesions seen in life.

Histologic changes are non-specific but include acanthosis, a mixed mononuclear perivascular dermatitis, sebaceous gland metaplasia and secondary superficial pyoderma¹.

Treatment

Flare factors

Ectoparasites

Fleas and Neotrombicula frequently complicate AD. Atopic dogs can also contract Sarcoptes. Demodicosis may be associated with immunosuppression particularly iatrogenic hyperadrenocorticism. Microbial infections Secondary infections should be identified and treated promptly. Topical therapy can reduce microbial populations and recurrence of infections. Immunosuppression may result in infections but control of inflammation usually reduces colonization and infection with Malassezia and staphylococci. Dogs that are very prone to pyoderma, however, can benefit from long term pulse antibiotic therapy.

Stress

Stress can exacerbate human inflammatory dermatoses, and this may be true in animals. There is anecdotal evidence that behavioral therapy and pheromones can help.

Environmental effects

Excesses of temperature and humidity, irritant surfaces or cleaning solutions etc. can all worsen skin diseases. Observant owners will often report associations.

Improving skin barrier function

Diet and the skin

Many atopic animals non-specifically improve following food trials, probably because high quality, essential fatty acid (EFA) enriched, single-protein sensitivity control and hydrolyzed hypoallergenic diets affect the skin barrier and/or skin immune system. Nutrients believed to be important include: •Zinc – decreases inflammation. •Long chain omega (n-3) EFAs – alter eicosanoids and decrease inflammation. •Inositol, choline, histidine, pantothenate, nicotinamide – improve epidermal lipid barrier formation. •Aloe vera and curcumin – up regulate fibroblasts, proteoglycan synthesis and TGF-β production, and decrease inflammation. In the author’s opinion, unpublished data from randomized cross-over studies have shown that Eukanuba Dermatosis FP and Royal Canin Skin Support diets significantly ameliorated clinical signs in atopic dogs.

Topical therapy

Topical therapy has a number of benefits although it is time-consuming. Physical removal of allergens is likely to be helpful. Hydration can be prolonged by using moisturizing shampoos and conditioners. These can also improve the skin lipid barrier. Colloidal oatmeal may also have a direct antipruritic action. Virbac’s Allermyl® range contains linoleic acid (improves the skin lipid barrier), vitamin E and mono-oligosaccharides (may reduce TNF-α production and prevent microbial adherence) and piroctone olamine (modulates the skin flora). Chitosanides and microspherulites help prolong retention and activity on the skin and coat. Other topical products that may be helpful in individual cases include ear cleaners and anti-microbial or anti-scaling shampoos. The exact balance of desired effects varies between individuals, so be prepared to try different products and/or alternate between antimicrobial and emollient shampoos.

Essential fatty acids (EFA)

Numerous clinical trials and studies have evaluated EFAs particularly the n-3 EFA eicosapentenoic acid (EPA) and the n-6 EFA gamma-linolenic acid (GLA). Supplementation can result in altered plasma levels and incorporation into cell membranes, which may lead to production of less inflammatory leucotrienes and prostaglandins and improved cutaneous lipid barrier. Recent studies, however, have not found consistent changes in plasma, subcutaneous fat or cutaneous EFAs following supplementation in atopic and healthy dogs, and no correlation with the clinical response (1-3). Clinical results have been variable in controlled trials, and no relationship between efficacy and ratio of n-3/n-6 EFAs have been proven, although high doses seem to be more effective. Recent studies have shown that high quality, EFA enriched diets are beneficial in canine AD although how much of this is due to anti-inflammatory activity or cutaneous barrier improvements is unclear (4).

Allergen specific therapy

Allergen specific therapy will only be appropriate in animals with identified sensitivities. The aim of allergen testing is to identify allergens for avoidance and immunotherapy, not to confirm the diagnosis.

Allergen avoidance

Allergen avoidance measures can result in a significant reduction in exposure to house dust mite (5). Whether allergen avoidance results in clinically significant improvement is controversial, although one uncontrolled study demonstrated that allergen avoidance was beneficial in canine AD (6).

Allergen specific immunotherapy (ASIT)

ASIT involves the administration of gradually increasing amounts of allergen by subcutaneous injection. The mechanism of action is unknown but it is thought that administering large doses of allergen in an unusual route (i.e. subcutaneous instead of epidermal) induces tolerance. Many studies (albeit mostly open or retrospective) have shown that 60-80% of dogs have a greater than 50% improvement following ASIT. The best results seem to occur with early treatment, although a 9-12 month trial is necessary to assess the response in each case. Animals on ASIT require careful supervision to control microbial infections and other flare factors, to administer anti-inflammatory treatment as required and to adjust the dose and/or frequency according to the clinical response (Figure 1). The exact protocol varies widely but usually involves repeated injections a few days to 1-2 weeks apart. Once the full dose is reached, the interval between injections can be extended. A rush protocol, where the initial loading course is given within a single day, was recently shown to be as effective as conventional ASIT in a small number of dogs (7). Recent reports also described starting with a full dose (monodose therapy). No adverse effects were seen in either case although the dogs were pre-medicated with an anti-histamine. Alum precipitated vaccines have a depot effect and require less frequent administration. Alum adjuvants potentiate IgE responses in experimental animals but no differences in efficacy between alum-precipitated and aqueous vaccines have been demonstrated in dogs. There are anecdotal reports of improved efficacy with low dose ASIT, but a controlled study, however, found no difference in efficacy between low dose and conventional alum-precipitated ASIT (8). If ASIT proves successful, the interval between injections can be extended. Increased pruritus before the next injection is due indicates that the interval is too long. The interval may also vary through the year, especially in pollen sensitive animals. Some dogs can be weaned off treatment, but most require maintenance injections every 1-2 months. Re-testing may reveal new sensitivities in dogs with initially negative tests, dogs <12 months old at the time of the original test, if there has been a poor response to ASIT or where a good response is not maintained. Re-formulating ASIT can be beneficial in these dogs. Adverse effects are uncommon. Injection site reactions and anaphylactic shock are very rare, although many dermatologists advise giving the first 5-6 doses in a veterinary clinic. Increased pruritus after an injection indicates that the dose is too high although mild reactions can sometimes be managed with antihistamines.

Anti-inflammatory therapy

Anti-inflammatory therapy is used as required to control residual pruritus and inflammation. Almost all atopics will require treatment in the short to medium term, but the dose, frequency and/or potency of drugs can be reduced if other treatments are successful in the long term.

Cyclosporine

Cyclosporine suppresses T-cells, which have been implicated in the pathogenesis of canine AD. I t also inhibits other key cells in allergic inflammatory reactions such as mast cells and eosinophils. This has profound effects on antigen presentation, IgE production, mononuclear cell activity and the development of inflammatory lesions, although at the doses used in canine AD, cyclosporine is immuno-modulating rather than immunosuppressive (Figure 2). Cyclosporine is rapidly absorbed and distributed. Bioavailability varies from 15-60% in individual dogs and is not affected by food. There is little correlation between trough levels and efficacy, and dose adjustments are made according to the clinical response rather than monitoring plasma levels. Metabolism is via the cytochrome P450 system. Numerous drugs can decrease metabolism, notably itraconazole and ketoconazole, which increases plasma concentrations, efficacy and the likelihood of adverse effects (Figure 3). Phenobarbital increases metabolism and decreases plasma levels. Cyclosporine is administered for canine AD at a dose of 5 mg/kg once daily. Controlled studies have shown that it is at least as effective as prednisolone and methyl-prednisolone (9,10), although this may take 2-3 weeks to become apparent. Glucocorticoids can be initially coadministered to achieve more rapid remission. Approximately one third of treated dogs require daily dosing, one third every other day and one third twice weekly to maintain remission. Using cyclosporine as part of an integrated management program can be more cost-effective than relying on it alone. The effect on intradermal testing and serology is thought to be minimal, although the data is sparse. Anecdotal data suggests that cyclosporine does not affect the response to ASIT any more than glucocorticoids although controlled studies have not yet been performed. Cyclosporine is well tolerated by the majority of dogs. Transient anorexia and vomiting are the most likely problems. Persistent vomiting is uncommon but may be eased by administering with food, and/or by using the gastrointestinal protectant sucralfate or H-2 blocking agents such as ranitidine. Other uncommon adverse effects include hirsuitism, increased shedding of hair and transient alopecia, gingival hyperplasia, papillomatosis, diarrhea, lameness and muscle tremors, and erythema and edema of the ears. These are largely dosedependent and reversible. The nephropathy, hepatopathy and hypertension seen in humans have not been recognized in dogs except at doses >20 mg/kg. Immunosuppression is a potential concern. Inhibition of cell-mediated immunity in particular could result in bacterial and protozoal infections, dermatophytosis and demodicosis. In practice, however, the risk appears to be very small and most atopic dogs experience fewer secondary infections following treatment. Feline and human patients on long term treatment have a small risk of developing lymphoma and cutaneous neoplasms. Lymphoplasmatoid dermatitis has been seen following doses >20 mg/kg and there is a single case report of lymphoma in an older dog following treatment for anal furunculosis. These have, however, not been reported in atopic dogs (11). Inhibition of T-helper cell function and β-cell activation could affect the response to vaccination. Some authors advocate withdrawing treatment for up to two weeks either side of vaccination, although this will lead to worsening of the skin condition. The pros and cons for each individual case should be discussed with the owner.

Phytopica™

Phytopica™, a compound derived from Rehmannia glutinosa, Paeonia lactiflora and Glycyrrhiza uralensis improved canine AD in a preliminary study (14). In a recent randomized, double-blind and placebo-controlled trial of 120 dogs Phytopica™ (200 mg/kg/day) appeared to be an efficacious, safe and palatable non-steroidal treatment for canine AD, although the effect was modest with most dogs achieving a 20-50% improvement in clinical signs (15). Responses are typically evident within four weeks (Figure 4). Adverse effects are self-limiting gastro-intestinal disturbances such as diarrhea and vomiting. This is generally a better safety profile than has been reported for other anti-inflammatory therapies (16).

Glucocorticoids

Corticosteroids, synthesized in the adrenal cortex, have glucocorticoid (anti-inflammatory and gluconeogenic) and mineralocorticoid (salt and water balance) activity. Glucocorticoids are simultaneously the most used and abused drugs in veterinary dermatology. They are cheap, easy to administer and highly efficacious but are associated with a plethora of side-effects (17,18). At pharmacological doses they inhibit the expression of genes encoding a variety of molecules involved in immunity and inflammation, resulting in rapid and profound immunosuppression and decreased inflammation. Most quoted doses are for prednisolone (Table 1); the dose for other steroids is calculated according to the relative potency. Steroids also vary in their mineralocorticoid activity and duration of activity, but that suppression of the hypothalamicpituitary- adrenal (HPA) axis may last longer than the therapeutic effect. Only prednisolone and methyl-prednisolone are suitable for long term alternate day dosing as their duration of activity should leave at least 12 hours for the HPA axis to recover. The formulation also has an impact: soluble esters (such as succinates and phosphates) have a rapid onset and shorter duration of action; acetates have a moderate onset and duration; and acetonides and dipropionates are long-acting depot preparations. Glucocorticoids are highly effective in canine AD, but must be used with care and, ideally, as a last resort. Exploring alternative approaches will help minimize the dose and frequency required. Genuine seasonal AD that requires 3-4 months treatment each year, however, can usually be managed successfully with minimal problems. Short courses (0.5-1.0 mg/kg once daily for 3-5 days) can also be administered to treat flares of inflammation in dogs otherwise well controlled on other medication. Topical treatment directs the steroid to affected skin and avoids the need for systemic therapy. Topical glucocorticoids can be used where inflammation is localized to relatively hairless skin, pyotraumatic dermatitis (‘hot-spots’) or in the ears and eyes. More potent products containing betamethasone etc. can be used once or twice daily initially, but hydrocortisone is better for long term, alternate day treatment. Fuciderm® (contains betamethasone) is a good choice as the gel formulation allows rapid penetration and drying. Systemic therapy is necessary with more severe or widespread lesions. 0.5-1.0 mg/kg prednisolone is given once daily until remission. You can then administer the same dose every other day and then reduce the dose by 50% every 7-14 days until the lowest maintenance dose is established; or, gradually wean the alternate day dose off, and then establish the lowest every other day maintenance dose. The only suitable systemic drugs for alternate day dosing are prednisolone or methyl-prednisolone, but triamcinolone, betamethasone or dexamethasone can be used to achieve remission in severe cases. Injectable preparations should not be used unless absolutely necessary, as it cannot be withdrawn, the dose cannot be altered, nor the hypothalamic-pituitaryadrenal (HPA) axis allowed to recover. Glucocorticoids will suppress reactions to intradermal allergen tests, although the effect on serology is believed to be less marked. It is currently recommended that you withdraw topical glucocorticoids for at least two weeks, short acting oral glucocorticoids for at least three weeks and longer acting injectable glucocorticoids for at least six weeks before allergy testing. Dogs on long term treatment or with iatrogenic hyperadrenocorticism may need considerably longer withdrawal times (Figure 5). Glucocorticoids are frequently administered to control inflammation during the induction phase of immunotherapy. This does not appear to affect the response rate although there are no controlled studies. Adverse effects arise from the glucocorticoid and mineralocorticoid activity as well as suppression of the HPA axis and endogenous steroid production. Common acute side-effects include polyuria and polydipsia. The risk of these problems developing can be reduced by using methyl-prednisolone, which has much less mineralocorticoid activity. Other acute sideeffects include polyphagia and weight gain (which can be managed using a low calorie diet), panting and behavioral changes (including dullness and, rarely, aggression). The onset of iatrogenic hyperadrenocorticism is dose and duration dependent, but there is a wide variation in tolerance between individuals. Immunosuppression and secondary infections are quite common with long term treatment. Inhibition of cell-mediated immunity can result in demodicosis, dermatophytosis and infections with intracellular organisms. Immunosuppression and alterations in cutaneous barrier function commonly result in superficial pyoderma. Production of dilute urine is a factor that contributes to cystitis. Some of these infections may be clinically inapparent, as steroid therapy may mask some of the associated inflammation and characteristic clinical signs such as pruritus or dysuria. Because humoral immunity is less affected, animals can develop adequate antibody titers following vaccination. For this reason, short term treatment may be used to control the clinical signs if cyclosporine has to be withdrawn because of routine vaccination.

Hydrocortisone aceponate

Hydrocortisone aceponate is a novel topical diester glucocorticoid for the treatment of pruritus in dogs. Topical diester glucocorticoids overcome many of the adverse effects traditionally associated with systemic or topical glucocorticoid therapy. They are rapidly absorbed and exert potent anti-inflammatory effects within the epidermis and superficial dermis. Metabolism within the dermis, however, ensures that very little active compound reaches deeper tissues and the circulation, minimizing skin thinning and systemic effects. The topical formulation, furthermore, eases topical administration. The small dose volume, very small droplet size and volatile carrier help to ensure quick and easy application, penetration of even haired skin and rapid drying with minimal cutaneous after effects. The spray is formulated such that two sprays from 10 cm away will penetrate the coat and treat a 10 x 10 cm (i.e. palm sized area of skin). Early studies (unpublished) demonstrated good efficacy and safety in short term treatment of various pruritic disorders in dogs including pyotraumatic dermatitis and f lea allergic dermatitis. An open-label pilot study and preliminary findings from a randomized, doubleblind, placebo controlled study found that Cortavance® was effective and well-tolerated in managing canine AD. One dog has suffered a contact reaction, but adverse effects have not otherwise been noted. Once daily administration was sufficient to induce remission, after which a proportion of dogs can be maintained on every other day therapy. Twice weekly administration, however, resulted in a relapse in most dogs.

Antihistamines

A large review of clinical trials (16) concluded that there is no more than fair evidence of medium efficacy for the first generation antihistamines clemastine and a combination of chlorpheniramine and hydroxyzine, and the second generation (non-sedating) drug oxatomide. There may however be some synergistic activity with EFAs and glucocorticoids. Adverse effects of first generation drugs are uncommon and are usually linked to drowsiness. Adverse effects to second generation drugs are more common and include gastrointestinal tract upsets and cardiac arrhythmias.

Prognosis

If left untreated, the degree of pruritus worsens, but atopic dermatitis is not life threatening unless intractable pruritus warrants euthanasia¹. Some cases may spontaneously resolve.

Links

• The Merck Veterinary Manual - Canine Atopy

References

1. Tilley, L P and Smith, F W K (2004) The 5-minute Veterinary Consult (Fourth Edition),Blackwell.
2. Beale, K M (2006) Atopic Dermatitis: Clinical Signs and Diagnosis. Proceedings of the North American Veterinary Conference 2006.
3. Willemse, T (2007) The Newest on Canine Atopic Dermatitis. Proceedings of the Southern European Veterinary Conference & Congreso Nacional AVEPA.
4. Merck & Co (2008) The Merck Veterianry Manual (Eight Edition), Merial.