Abstract

Canine atopic dermatitis (AD) is a multifaceted disease that presents with the hallmark sign of itching. Research continually reveals new aspects of allergic skin disease, from elements of its pathogenesis and improvements in diagnostic criteria, to more effective and safer treatments. Basic elements of treatment include parasite and infection control, medical management of inflammation and pruritus, support of epidermal barrier function, and correcting immunologic imbalances with allergen-specific immunotherapy. These treatments must be combined in a multimodal fashion to provide optimal patient response over many years, with minimal chances of adverse effects. As our scientific understanding of AD evolves, treatment approaches are being developed that specifically target newly identified abnormalities in pathobiology in atopic patients.

Key Facts

 AD has complex pathobiology and requires multimodal treatment for maximal success.

 In daily practice, veterinarians typically anchor treatment protocols with drugs, such as corticosteroids, that are targeted at stopping pruritic behaviors (scratching, itching, and rubbing) and deceasing dermal inflammation. This may be driven by the need to address the owner's complaints that persistent itching and scratching in their dog is detrimental for their pet and disrupts the quality of life of the pet and the owner.

 While decreasing pruritus remains a key therapeutic objective for veterinarians treating atopic dogs, they understand that successful therapy for AD typically combines several modes of therapy aimed at both the primary disease as well as the secondary complications. As a result, they frequently utilize multimodal treatments that are flexible and individualized to the patient in order to maximize therapeutic response and increase pet owner satisfaction.

 Current treatment regimens for AD focus on addressing multiple aspects of the disease pathogenesis:

 Abnormalities in the epidermal barrier

 Environmental exposure to potential allergens

 Controlling concurrent infections or colonization with common pathogens such as Staphylococcus pseudintermedius or Malassezia yeast

 Controlling the immune responses to allergenic stimulation

 Controlling stimulation of the itch response

 Contemporary, multimodal treatment protocols can include one or more of the following therapeutics based on individual patient needs:

 Topical therapies such as shampoos or nutritional supplements to reduce barrier permeability and enhance barrier function

 Anti-infective topical or systemic antimicrobials to treat secondary infection

 Hypoallergenic diets

 Anti-pruritic therapy to control itch and scratching, including oral treatment with oclacitinib

 Allergen-specific immune therapy (ASIT) to enhance the patient's immune response to specific allergens

 Managing inflammation by moderating the animal's immune response using drugs such as cyclosporine or corticosteroids

 Future options for treating AD may include biological therapies such as monoclonal antibodies, aimed at specific elements of the allergic response, such as cytokines.

The many new factors, recently uncovered, that are involved in the pathogenesis of canine AD continue to add evidence that this is a multifactorial disease, which necessitates a multifactorial approach to treatment. But how, exactly, do these new facts about pathogenesis translate into treatment protocols? Clearly, treatment approaches for AD must be individualized and flexible, combine several modes of therapy, and be aimed at both the primary disease and secondary complications, to maximize success and client satisfaction. Our goal with each patient is to find just the right combination of therapies to provide lifelong management that is effective, affordable, convenient, and with as few adverse effects as possible.

Changing Views of Treatment

Historically, management of AD has been aimed at the end process of the disease - in other words, focused on anti-inflammatory therapies. "Managing inflammation" has been the first goal of therapy. This traditional approach was a rather "blunt instrument" often consisting principally of oral corticosteroids, with antihistamines or fatty acids as possible adjuncts. As our understanding grew, we gained additional tools to manage the inflammation (for example, the oral and topical calcineurin inhibitors such as ciclosporin) and effective topical steroid products that could manage inflammation with less systemic effect. We also gained a renewed understanding of the importance of treating secondary complications such as bacterial and yeast infections. All of these approaches, even as they evolved, were still completely reactive - reacting to the inflammatory process, after it had already become well established in the skin.

Our newer approach to long-term treatment of AD encompasses a broader, "whole patient" approach, stressing a multifaceted approach, based on a multifaceted pathogenesis, and multifaceted clinical signs that are likely different in each patient. In addition, where possible we now stress a proactive approach to treatment - in other words, correcting the underlying pathogenesis of the disease where possible, preventing acute flares where we can, and forestalling the development of chronic inflammatory changes in the skin that become much more difficult to reverse.

Start with the Basics: Parasite Control, Infection Control, and Bathing

Many dogs with AD will have concurrent flea sensitization. Thus, routine prophylactic antiparasitic treatment (for example, the monthly topical or oral preparations) is advised for all canine AD patients. In addition, most dogs with AD are very susceptible to secondary infection with both staphylococci and yeast organisms. Treatment must focus on not only initial elimination of the infections, but prevention of future episodes of infection. This is most often accomplished by frequent use of topical antimicrobial therapy. Shampoo or spray application of chlorhexidine or chlorhexidine/azole preparations weekly is recommended.

Bathing helps! Studies have shown that frequent (weekly to twice weekly) bathing with a non-irritating, emollient shampoo can have a limited antipruritic effect;^1,2 it also washes away debris, environmental allergens, and organisms from the skin. No single topical formulation has shown clear superiority in this regard. Since recurrence of secondary infections is often a problem, the choice for a maintenance shampoo often dictates use of an antimicrobial formulation, as above.

Beginning Medical Management

Antihistamines

Medical management of the AD often begins with the safest drugs to administer longer-term. Though from an evidence-based standpoint we have no confirmation that antihistamines are beneficial in AD, many clinicians believe that they benefit a small number of patients and that they are always worth trying. Recent, better-designed and controlled studies have shown some success in dogs with the antihistamines dimetinden, fexofenadine, and a combination of hydroxyzine and chlorpheniramine.^3,4 However, the magnitude of relief that antihistamines appear to provide remains minimal. Combination with anti-inflammatory fatty-acid supplements may provide additional benefit. There is no evidence that the newer, nonsedating antihistamine drugs now commonly used in human allergy have any additional benefit for animal use.

Anti-inflammatory Fatty-Acid Supplementation

EFA supplements remain a cornerstone of conservative management. Their effects may occur through their weak anti-inflammatory effects or through possible effects on epidermal barrier function. Though as sole therapy they have minimal efficacy, studies demonstrate they may have synergistic effects with antihistamines (improved efficacy) and with glucocorticoids or ciclosporin (dose-sparing effect). Because they are relatively inexpensive, safe, and easily administered, many dermatologists advise that all atopic pets should receive enhanced levels of EFA.

Dose is typically based on the total anti-inflammatory content, which includes EPA, GLA, and DHA. The total (DHA+EPA+GLA) should be administered at a dose of at least 25–35 mg/kg/d. This can be accomplished with supplements or, increasingly, with EFA-enhanced diets. The latter may be a more cost-effective approach that enhances client compliance, but it is sometimes difficult to ascertain which foods have enough EFA content to provide the required dose. Clients must be warned that many over-the-counter supplements (such as salmon or coconut oils) have only very small amounts of the desired EFA. There is little evidence that the ratio of omega-3 to omega-6 EFA is very important in skin disease. It is also important to advise clients that beneficial effects take at least 1–2 months to be seen.

Pillars of Medical Management: What Really Helps

Corticosteroids

Atopic dermatitis is generally quite responsive to corticosteroid drugs. They are sometimes satisfactory in pets with highly seasonal disease, and are an excellent short-term treatment for acute flares. Oral prednisolone, prednisone, or methylprednisolone at 0.5–1 mg/kg/d are the preferred treatments; repeated injections of long-acting corticosteroids should be avoided. The chief disadvantages of longer-term use of corticosteroid drugs include development of steroid resistance or "tachyphylaxis," and adverse effects (of both annoying and medically serious varieties). Animals receiving longer-term oral corticosteroids should have a urine culture performed twice annually to identify silent urinary tract infections. It is wise to check liver enzymes annually.

Topical hydrocortisone aceponate spray is also very useful. This corticosteroid is metabolized entirely in the skin and is not absorbed into the systemic circulation, thus sparing the pituitary-adrenal axis and liver. It can be used for "trouble areas" of atopic dermatitis, such as the ventrum, feet, anal area, etc., or can be sprayed over broader regions of the body.

Ciclosporin A Modified (CsAM)

The calcineurin inhibitors work by inhibiting production and action of cytokines, and through other mechanisms as well. Clinical trials of ciclosporin in dogs with AD demonstrate that this drug has efficacy equal to that of oral prednisone.⁵ The starting dose is 5 mg/kg/day, which can be given as a single dose or divided into multiple doses. After the first month of treatment, in some dogs the dose can be decreased. Perhaps 25% of patients will have some initial gastrointestinal discomfort from CsAM. In most cases, this will abate within a few weeks. Therapy with CsAM is remarkably free from long-term adverse effects. Gingival hyperplasia is a known adverse effect of longer-term, higher-dose CsAM therapy, but occurs only rarely (1–2% of patients) at the doses typically necessary for AD. Protocols for combination of CsAM with ketoconazole for long-term management of AD have not been developed. A major concern here would be potential for development of hepatotoxicity with long-term ketoconazole treatment. Long-term use of CsAM combined with systemic corticosteroid drugs has been associated with development of fatal opportunistic fungal infections, so should be avoided. CsAM typically acts relatively slowly, often taking 2–4 weeks to reach maximum effectiveness. Therefore, many dermatologists begin a short (2-week) tapering course of oral prednisolone along with CsAM for faster patient relief; this appears both safe and effective.⁶ Therapeutic monitoring (serum chemistries, blood counts, or CsA serum concentrations) is neither recommended nor necessary when using CsAM for AD patients.

Janus Kinase Inhibitors

JAK/STAT Signaling and Oclacitinib Maleate

One of the most exciting new classes of drugs in medicine is the kinase inhibitors (KIs). These drugs represent a new and completely different way to change cellular function. Development of KIs is only in very early stages of infancy. It is likely that many drugs in this group will be developed over the coming years, aimed at treating a variety of neoplastic, inflammatory, and immunologic diseases. Thus, it is important for veterinarians to understand the basis of these new and exciting molecules.

The most recent molecular target to receive attention is the family of kinases known as JAK. There are four Janus kinases in the family - JAK1, JAK2, JAK3, and TYK2. The JAKs function to communicate a signal from a cell surface receptor to the nucleus, and many inflammatory pathways (especially cytokines and their receptors) use JAKs for signaling. JAKs function in pairs (e.g., JAK1/JAK2). When activated, JAKs next interacts with any of several STATs, another family of molecules, and the STAT proteins translocate to the nucleus to regulate transcription. There are many different JAK/STAT combinations functioning in many different tissues to signal a very large variety of end responses.

In considering function of JAK/STAT signaling, closer examination of the role of cytokines in inflammation and pruritus is useful. Cytokines (such as interleukins or interferons) are protein messengers used for intercellular communication. They are produced by cells and then travel to other cells where they bind to membrane receptors to convey their signals and induce biologic responses. It is well recognized that cytokines, such as IL-2, IL-4, IL-5, IL-12, IL-13, IFN-gamma, and many others, are important mediators of inflammation in allergic disease and are targets of therapies, such as the calcineurin inhibitors (i.e., ciclosporin).

Recently, IL-31 has been identified as a key cytokine in pruritus.⁷ Several lines of evidence demonstrate its importance in a variety of pruritic skin diseases. IL-31 is secreted by the "pro-allergic" T helper 2 lymphocytes (among other cells) and works by binding to a receptor, which triggers a JAK/STAT pathway. When the pathway is activated, the result is a vicious cycle of neuroimmune interaction and pruritus. This raises the intriguing possibility that, if we could block this particular JAK/STAT pathway, we might be able to block the pruritic response.

Oclacitinib maleate (Apoquel), a JAK inhibitor, has been studied in a variety of models of pruritus and has shown the ability to suppress pruritic responses rapidly and effectively, in some cases better and quicker than prednisolone.^8,9 At therapeutic doses, oclacitinib inhibits predominantly JAK1 and spares JAK2-dependent processes such as hematopoiesis. Controlled clinical trials of oclacitinib in the treatment of both canine allergic dermatitis (flea, food, contact) and canine AD have shown promising results. Results in head-to-head studies against either prednisolone or ciclosporin show the drug to be equally effective in control of itch and inflammation, and to have a very rapid onset of action with relief sometimes apparent within hours of oral administration. Oclacitinib maleate is indicated for control of acute or chronic pruritus in dogs over 12 months of age. Recommended dosing consists of twice-daily administration for up to 2 weeks, followed by once-daily dosing for longer-term use. A few dogs seem to worsen slightly when switched from twice to once daily, probably related to the short half-life of the drug (4 hours in the dog). Overall, it appears that at least 60–70% of allergic dogs receiving the drug have rapid, substantial, and prolonged relief of their clinical signs.

Veterinary dermatologists often comment that the drug is very useful as part of a multimodal treatment approach, and that some dogs with even very recalcitrant disease have shown remarkable response. Short-term adverse effects have been limited to GI disturbance in a very few dogs, though the adverse effects occur nearly as frequently in placebo-treated dogs. There is no specific organ toxicity associated with Apoquel; therefore, no specific laboratory monitoring is advocated, though good medical practice dictates that all dogs receiving this drug should be examined at least once annually. Apoquel has been administered for as long as 3 years in some dogs; in longer-term studies, occasional patients have developed benign or malignant neoplasms, but no more often than would be expected for dogs in the studied age range. The drug has been limited to use in dogs 12 months or older, mostly because in one high-dose safety study with young laboratory dogs, generalized demodicosis developed in some patients. Oclacitinib has not been evaluated in combination with other drugs such as systemic corticosteroids or ciclosporin; concurrent use should be avoided with these drugs at this point. However, it can be used safely along with antibiotics, antihistamines, antifungal drugs, NSAIDs, allergen-specific immunotherapy, and many other medications, and vaccination of treated dogs is effective. Apoquel does not appear to interfere with serologic or intradermal allergy tests. As with other immunosuppressive treatments, it should not be used in the face of a severe infection, demodicosis, or with active malignancy.

Biological Therapies as Options

When medication does not help completely or adverse effects develop, biologic therapies can be considered as options. These treatments have varying availability throughout the world. One category that has been studied quite well is use of interferons. Recombinant canine interferon-gamma (Interdog, Toray) is marketed in Japan as an effective (though expensive) injectable treatment.¹⁰ Recombinant feline interferon-omega (Virbagen Omega, Virbac) administered subcutaneously at 1–5 million units 3 times weekly for 1 month, then once monthly, has shown limited efficacy in canine AD.¹¹

Several new biological therapies - usually monoclonal antibodies - are in development for atopic dermatitis in both humans and dogs. The first product to appear on the market is likely to be an anti-IL-31 monoclonal, which reduces or eliminates this cytokine from tissues, therefore reducing pruritus. The product has received a conditional license in the USA and is being used by U.S. dermatologists with great success.

Fixing What's Wrong: Epidermal Barrier Function

Because many of the abnormalities recently identified in AD patients involve some aspect of the epidermal barrier, it is useful to examine this concept more closely. The epidermal barrier has many functions, including protection against mechanical trauma and ultraviolet radiation, prevention of water loss through the skin, and preventing entry of external substances (toxins, drugs, irritants, allergens...) into the body. A recent view is to consider the epidermal barrier to consist of two basic elements: a physical permeability barrier, as described above, but also an antimicrobial barrier. It is now recognized that the epidermis and associated glandular structures are also very active in secreting a wide variety of substances involved in defense against cutaneous microorganisms. These substances include antimicrobial lipids and specific immunoglobulins, as well as antimicrobial peptides such as the defensins and cathelicidins. Together with the tough mechanical structure of the stratum corneum, these molecules provide a formidable defense against colonization and infection...or at least, they will provide this in normal individuals!

There is no question that the epidermal barrier functions are abnormal in atopic people. Early research on morphologic evaluations (as performed by electron microscopy), analysis of lipid components of the epidermis, and functional evaluations (as performed by the technique of transepidermal water loss) consistently showed that the stratum corneum in atopic human beings is defective or "leaky" compared with normal people. As research progressed, it was determined that not only the permeability barrier, but also the antimicrobial barrier was defective - the skin of atopic people produces much less antimicrobial peptide than normal. More recently, genetic analysis has revealed specific genetic defects in critical functional proteins in the epidermis. In fact, the more the concept of "barrier function" is examined, the more it becomes obvious that barrier function is abnormal in AD, and this is a critical part of the pathogenesis of the disease.

From a clinician's standpoint, the obvious question becomes "can we improve clinical signs of AD by somehow improving barrier function?" In human AD, application of emollient preparations to the skin is an important and basic element of treatment, and unquestionably helps relieve symptoms over time. In dogs, studies have shown that the lipid composition of the stratum corneum can be modified by either dietary or topical means.^12,13 Manipulation of the diet by altering its fatty acid composition affects the composition of skin lipids and may possibly help barrier function.

Topical modification of barrier function is an active area of research in veterinary medicine. Initial research has shown that application of topical lipid preparations can result in improvement of the intercellular lipid lamellar structure and composition and can be associated with limited clinical improvement, though such improvement typically takes months.

Fixing What's Wrong: Allergen-Specific Immunotherapy

One of the most valuable, and possibly most underused, specific allergy treatment methods is allergen-specific immunotherapy (ASIT) - "allergy shots" or the newer sublingual (SLIT) formulation "allergy drops." Allergen-specific immunotherapy is a treatment for AD in dogs and cats wherein extracts of allergens to which the patient is sensitive are administered, in gradually increasing amounts, to lessen or reverse the hypersensitivity state. It is the only treatment we have that can directly reverse part of the underlying pathogenesis of the disease, and it can do this at reasonable cost, with success in most animals, mostly without adverse effects, and for the animal's lifetime. Chief disadvantages include that it takes several months or more to begin working, and that it is not always effective.

Most effects of ASIT are believed to be allergen-specific rather than nonspecific. Thus, accurate testing to identify the offending allergens in each patient is of paramount importance to successful immunotherapy. In particular, the clinician must strive to avoid false-positive allergy test results, which would result in including an allergen in the patient's mixture that is not relevant to that individual's disease.

The exact protocol and schedule for administration varies according to the allergen preparation; generally, the extract manufacturer will provide an appropriate schedule. Treatment is given year-round, and the minimum initial trial period should be 12 months. As far as is known, concurrent treatments with antihistamines, fatty acid supplements, cyclosporine, or low-dose glucocorticoids will not interfere with response. Treatment is generally considered to be lifelong, although discontinuation after 2–3 years can be attempted if the animal has responded well. Expected response rate to either the injection or sublingual formulation is the same - approximately 60–70% good-to-excellent response (the latter defined as at least 50% improvement in clinical signs). Response can be seen as soon as 1 month, but more typically takes 3–6 months to occur, and the maximum response may take at least 1 year. One practical difference between the formulations is that SLIT usually must be administered twice daily, every day, whereas the injections are often given once every 7–14 days. Adverse reactions to ASIT include localized itching at the site of administration and transient worsening of the pruritus for 12–24 hours after each treatment (in about 5–10% of patients). Generalized anaphylaxis occurs in <1% of dogs and cats and is rarely life-threatening. The SLIT formulation has some strong advantages over the injection formulation, including needle-free administration and relative freedom from adverse reactions including anaphylaxis.

In Conclusion

The last few years have seen a remarkable new dawn for therapy of allergic diseases. As new therapeutic targets continue to be uncovered, and new treatments developed against them, we are seeing a tremendous increase in our ability to provide safe and effective lifelong treatment for AD in both animals and humans. In veterinary medicine, it is important for practitioners to be aware of and understand these therapies, as they are more and more likely to become routine in the years ahead.

References

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9.  Gadeyne C, Little P, King VL, Edwards N, Davis K, Stegemann MR. Efficacy of oclacitinib (Apoquel®) compared with prednisolone for the control of pruritus and clinical signs associated with allergic dermatitis in client-owned dogs in Australia. Vet Dermatol. 2014;25:512–518.

10. Yasukawa K, Saito S, Kubo T, Shibasaki Y, Yamaoka K, Hachimura H, et al. Low-dose recombinant canine interferon-gamma for treatment of canine atopic dermatitis: an open randomized comparative trial of two doses. Vet Dermatol. 2010;21:41–48.

11. Carlotti DN, Boulet M, Ducret J, Machicote G, Jasmin P, Reme CA, et al. The use of recombinant omega interferon therapy in canine atopic dermatitis: a double-blind controlled study. Vet Dermatol. 2009;20:405–411.

12. Popa I, Pin D, Remoue N, Osta B, Callejon S, Videmont E, et al. Analysis of epidermal lipids in normal and atopic dogs, before and after administration of an oral omega-6/omega-3 fatty acid feed supplement. A pilot study. Vet Res Commun. 2011;35:501–509.

13. Popa I, Remoue N, Osta B, Pin D, Gatto H, Haftek M, et al. The lipid alterations in the stratum corneum of dogs with atopic dermatitis are alleviated by topical application of a sphingolipid-containing emulsion. Clin Exp Dermatol. 2012;37:665–671.