Canine atopic dermatitis (CAD) is the name given to describe a genetically predisposed inflammatory and pruritic skin disease with characteristic clinical signs, most commonly driven by an IgE/antibody associated reaction (Canine Atopic Task Force 2006). The pathogenesis of the disease is much more complex as dogs with the same set of clinical signs but with no demonstrable allergen-specific IgE exist, giving rise to the term atopic like dermatitis by Halliwell (2006), also known as intrinsic atopic dermatitis in the human literature. Human AD is considered to be a multifactorial disease characterised by pruritus, immunodysregulation, disrupted epidermal barrier function and IgE mediated sensitisation to food and environmental allergens (Misery 2011).

A similar multifactorial pathogenesis appears to be operating in canine atopic dermatitis and this explains why a ''one size fits all' approach is unsuitable and inadequate to achieve effective long-term control of the disease.

Pathogenesis

IgE-Mediated Response

The pathogenesis of CAD that remained dogma for many years was a type I hypersensitivity where dogs would become sensitised to environmental allergens and this would trigger the production of allergen-specific IgE antibodies. These would bind to mast cells and basophils in the dermis. Reexposure to the allergen would trigger mast cell and basophil degranulation and the release of a range of inflammatory cytokines causing erythema and pruritus.

Whilst it is clear that IgE plays an important role in CAD, it is only part of the picture and the current proposed pathogenesis is more complex. Recent evidence suggests that the major route of allergen exposure is via percutaneous absorption with barrier dysfunction allowing increased allergen entry. Once the allergen enters the epidermis it binds to the epidermal Langerhans cells where it undergoes internal processing and is presented to naïve T cells in the draining lymph nodes. In allergic individuals this leads to Th2 differentiation/polarisation and these Th2 lymphocytes release cytokines including IL-4, IL-5, IL-13 that stimulate IgE production by B cells that bind to cutaneous mast cells. Reexposure to allergens causes mast cell degranulation, cytokine release along with homing of T cells to the epidermis. This leads to cutaneous inflammation, erythema and pruritus (Marsella et al. 2012). However, it has become clear that in addition to this (more complex) immune response, both epidermal barrier dysfunction and infection play an important and interrelated role in the pathogenesis and severity of disease.

Barrier Function

The epidermis is an extremely active site of lipid synthesis. Lipids are important in barrier function, stratum corneum (SC) water holding, cohesion and desquamation of corneocytes and control of epidermal proliferation and differentiation. The three most abundant lipid species in the stratum corneum are cholesterol, ceramides and free fatty acids. Ceramides are the most important lipid component for the lamellar arrangement of the stratum corneum and consequently as a barrier function as they allow stretching and bending. The outermost layer of the epidermis is the stratum corneum (cornified layer) and disruption to this layer reduces the barrier to pathogens and allows moisture loss.

There is increasing evidence that animals with CAD have abnormalities in their barrier function and that these changes contribute significantly to the disease severity. It is not yet clear if this is a primary (i.e., genetic) or secondary (to atopic inflammation) change. Some of the changes that have been identified so far include: abnormal intracellular lipid lamellae, abnormal stratum corneum morphology, abnormal and reduced ceramide content (especially ceramide 1), abnormal filaggrin (an important protein necessary to maintain stratum corneum hydration) expression (Olivry 2011). The consequence of this impaired barrier function is an increase in the transepidermal water loss along with increased allergen penetration into the skin, stimulation of the skin immune system and increased risk of cutaneous infections.

Role of Infections

During inflammation, antimicrobial peptides, such as defensins and cathelicidins, are released by inflammatory cells and keratinocytes. In atopic humans there is a lower level of these antimicrobial peptides. This - together with the fact that there is a greater adherence of staphylococcal bacteria to keratinocytes of atopic individuals, localised defects in barrier function, altered microenvironmental humidity, a Th2-skewed immune response suppressing an effective antimicrobial immune response - makes atopic individuals more prone to skin infections. Bacterial exotoxins can also act as superantigens and augment the inflammatory response and worsen pruritus. In dogs, hypersensitivity to Malassezia spp. has also been recognised in recent years. All this leads to more severe pruritus and skin trauma.

In addition, bacteria can produce ceramidases and proteases that lead to further reduction in the stratum corneum, creating a self-perpetuating cycle of disruption in barrier function and inflammation.

The ongoing debate regarding the pathogenesis of AD is whether it is an 'inside-outside' process (primary immune defect leading to inflammation), 'outside-inside' (primary barrier dysfunction leading to inflammation) or 'inside-outside-inside' (genetic barrier defect leads to atopic cutaneous inflammation that leads to further barrier dysfunction). Regardless of this, as Marsella et al. (2012) state, "the key to understanding this complex disease may lie in the fact that different aspects may be important at different stages of development and that overlap exists."

From a practical/clinical perspective this means that all of the potential components that contribute to the pathogenesis (immune dysfunction, infection, epidermal barrier disruption) need to be identified and considered in the diagnosis and eventual treatment plan for successful control.

Clinical Signs and Diagnosis

The difficulty of this disease is that no clinical sign is pathognomonic. As a consequence there have been a number of sets of diagnostic criteria proposed over time that can be used once other causes of pruritus have been eliminated. The first was by Willemse in 1986 that called for 3 major and 3 minor clinical signs to be present.

Prelaud et al. (1998) defined five major criteria: corticosteroid sensitive pruritus, ear pinnae erythema, anterior bilateral erythematous pododermatitis, cheilitis and first symptoms appearing between the ages of 6 months and 3 years. It is suggested that the sensitivity and specificity of diagnosis on the basis of the presence of at least three major criteria was about 80%.

The latest has been proposed by Favrot et al (2010) with 2 sets of criteria.

The sensitivity and specificity varied depending on which set was used and how many criteria were included in the diagnosis:

When the sensitivity and specificity are examined, it can be seen that an incorrect diagnosis could be made in every fifth pruritic dog; therefore, these criteria must only be used after a complete and thorough elimination of all other causes of pruritus. As the signs of CAD are clinically indistinguishable from cutaneous adverse food reaction, a food elimination trial should be performed to rule this out before a diagnosis of CAD is made (Favrot et al. 2010).

Treatment

It is beyond the scope of these notes to detail the treatment of CAD so the reader is directed to 2010 treatment guidelines that were produced by the International Task Force on Canine Atopic Dermatitis and are free to download (http://onlinelibrary.wiley.com/doi/10.1111/j.1365-3164.2010.00889.x/suppinfo). However, the following are some of my thoughts on the treatment of this complex disease. Due to the complex pathogenesis of the disease, there cannot be a simple 'recipe' that will be effective in all cases. The treatment must identify the relative importance of the three fundamental elements of the disease, namely immune dysfunction, epidermal barrier disruption, and infections. The presence and relative importance of each may also vary over time, and this must also be taken into consideration.

1. Infection Control

There are very commonly either bacterial (predominantly Staphylococcus spp.), Malassezia infections or both present. If there are lesions that are consistent with a bacterial infection (papules, pustules, epidermal collarettes) or there are increased numbers of bacteria on cytology, appropriate systemic antibiotics need to be administered. Generally the duration of treatment is 3 weeks (time to cure plus 7–10 days). Shorter treatment course will commonly see a relapse in infection as soon as the antibiotics are stopped.

In addition to systemic antibiotics, topical antiseptics (chlorhexidine, benzyl peroxide, iodine, triclosan) can be used. These can be applied whilst the antibiotics are administered and then continued on a weekly basis to try and prevent infection relapse.

If the cytology shows increased numbers of Malassezia organisms, then treatment should be initiated. In cases of marked lichenification, systemic medication (itraconazole 5 mg/kg q 24 hrs or terbinafine 20 mg/kg q 12 hrs) may be started and used for the first 2–3 weeks and then topicals (miconazole, ketoconazole, enilconazole) applied to prevent relapse.

2. Barrier Dysfunction

Whilst there are only limited studies to document the benefits of trying to correct barrier disruption, I will try and correct it in affected individuals and feel that it is a very important component of the overall treatment plan, because theoretically repairing the barrier will decrease allergen absorption, decrease cytokine production by the epidermis, and decrease entry of bacterial and environmental proteases. The effect is variable and the same treatment will produce different responses. It is also important to note that the application of topical barrier repair products has been shown to lead to increased disruption in some. So if the owner reports deterioration following treatment, the product should be discontinued or changed.

Oral essential fatty acid (EFA) supplementation (omega 3 and 6 oils) can be used, either as a supplement to the existing diet or contained within a commercial 'skin support' diet of which there are several alternatives. I will also occasionally use topical EFA application in animals that are fussy eaters. Kirby (2008) looked at the effect of feeding high-fat diets to dogs. The high-fat diets contained 13%, compared to control diets containing 9%.

Three high-fat diets were used:

1.  High in saturated fat

2.  High in omega 6 fatty acid

3.  High in omega 3 and 6 mix

All diets improved the skin and coat, but a significant difference took 12 weeks to become clinically apparent. The diet high in omega 6 gave better coat condition, whilst the diets high in both omega 3 and 6 resulted in both better scale and softness measures.

The practical message to take away from this study is that a mix of omega 3 and 6 gives the best results for improvement of the skin condition.

There are a range of topical barrier repair products available, but most share the same active ingredients and so there is no need to stock multiple products with the same ingredients. The actives and actions are listed below:

 Moisturising action

 Occlusives

 Fractionated lanolin

 Petrolatum

 Paraffin

 Soybean, grapeseed oil

 Propylene glycol

 These agents form a hydrophobic layer that traps water in the stratum corneum.

 Humectants/hygroscopic agents

 Sorbolene/glycerol (glycolic acid)

 Propylene glycol

 Urea

 Lactic acid

 Colloidal oatmeal

 These agents draw water from environment and deeper dermis and some also have a keratolytic effect.

 Emollients

 Fill spaces between corneocytes

 Create smooth surface

 Increased cohesion

 Flattening of curled edges

 Examples

 Lanolin, mineral oil, petrolatum

 Barrier repair

 Ceramide moisturisers

 Phytosphingosine

 Phytosphingosine-salicyloyl

 Potentiated pro-ceramide

 Topical application increases SC ceramide levels

 Antimicrobial action (M. pachydermatis)

 Antiinflammatory activity (decreases IL-1, TNF-alpha and thromboxane release)

I tend to recommend weekly application of a product, although this can be increased in more severe cases.

3. Immune Dysregulation

The treatment of this aspect of the disease falls into 2 broad categories, namely pharmacotherapy or immunotherapy. Olivry and Mueller (2003) published an evidence-based review of the various therapies that have been proposed and came to the following conclusions:

Allergen-Specific Immunotherapy (ASIT)

ASIT is the most common method of control used by specialist dermatologists for CAD. It involves the injection of native allergens at increasing concentration to alter the immune response. The exact mechanism of action is still under debate but is thought to relate to a change in the lymphocyte response to a better Th1:Th2 balance with increased IgG production, T cell anergy. However, it is vital to understand that it is not as simple as merely starting all animals suspected of atopy on immunotherapy and following a rigid standardised protocol. For successful treatment outcomes there must be good patient selection, good owner compliance, identification and control of other contributing factors (barrier disruption and infections) and appropriate allergen selection (made on the basis of knowledge of the patient's environment, pollination periods and seasonality of disease). Reported efficacy ranges from 52–100% depending on the report, but in our hands we find a response in 60–70% of cases. The time to improvement varies, but we will generally see improvement by around 6–8 weeks, which corresponds to the end of the initial buildup phase of the treatment. Rush induction protocols (where the injections are given every 30 minutes for 6–8 hours) significantly reduce this lag phase. If the treatment has been successful (as measured by improvement in clinical signs and/or reduction in concurrent medication), the vaccine is continued for at least 2 years. At that point some animals are able to stop immunotherapy and remain well controlled, whilst most need to remain on immunotherapy to maintain control.

The experience of the veterinarian managing the case can also have a significant impact on the outcome. Nuttal et al. (1998) demonstrated that cases managed by specialist practices had a significantly better outcome (95% vs. 60%) to externally managed cases. Compliance was also better in referred cases and similar findings have been seen in human studies. The differences are most likely due to increased client communication, increased understanding of the disease pathogenesis and ability to "fine tune" the protocol to the individual patient. However, good results should still be expected in cases where the immune dysfunction is the critical component of the clinical presentation.

Future Therapies

As the pathogenesis becomes better understood, new targets for therapy emerge. There is increasing evidence supporting synergism between the nervous and immune systems in the skin. Resident immune cells (e.g., Langerhans cells, mast cells) and transient cells (T lymphocytes) are associated with nerve fibres. When the immune cells are activated they can release substance such as neuropeptides, cytokines (e.g., IL-31) and neurotrophins that can directly stimulate the nerve fires. The nerve fibres in turn can release signalling molecules that can modulate the inflammatory response (Marsalla et al. 2012). New products are in development that can target the production of the proinflammatory cytokines. An example of this is oclacitinib, a selective Janus kinase inhibitor. This has been shown to inhibit the pruritogenic effects of IL-31 in dogs and may prove to be an effective treatment for the pruritic allergic skin diseases.

References

1.  Favrot C, Steffan J, Seewald W, Picco F. A prospective study on the clinical features of chronic canine atopic dermatitis and its diagnosis. Vet Dermatol. 2010;21:23–30.

2.  Halliwell R. Revised nomenclature for veterinary allergy. Vet Immunol Immunopathol. 2006;114:207–208.

3.  Kirby NA, Hester SL, Rees CA, et al. Skin surface lipids and skin and hair coat condition in dogs fed increased total fat diets containing polyunsaturated fatty acids. J Anim Physiol Anim Nutr. 2009;93(4):505–511.

4.  Marsella R, Sousa CA, Gonzales AJ, Fadok FA. Current understanding of the pathophysiologic mechanisms of canine atopic dermatitis. J Am Vet Med Assoc. 2012;241(2):194–207.

5.  Marsella R, Olivry T, Carlotti D. Current evidence of sin barrier dysfunction in human and canine atopic dermatitis. Vet Dermatol. 2011;22:239–248.

6.  Misery L. Atopic dermatitis: new trends and perspectives. Clin Rev Allergy Immunol. 2011;41:296–297.

7.  Olivry T, Mueller RS, International Task Force on Canine Atopic Dermatitis. Evidence-based veterinary dermatology: a systemic review of the pharmacology of canine atopic dermatitis. Vet Dermatol. 2003;14:121–146.

8.  Olivery T, DeBoer DJ, Favrot C, et al. Treatment of canine atopic dermatitis: 2010 clinical practice guidelines from the International Task Force on Canine Atopic Dermatitis. Vet Dermatol. 2010;21:233–248.

9.  Olivry T. Is the skin barrier abnormal in dogs with atopic dermatitis? Vet Immunol Immunopathol. 2011;144:11–16.

10. Prelaud P, Guaguere E, Alhaidari Z, et al. Reevaluation of diagnostic criteria of canine atopic dermatitis. Revue de Médecine Vétérinaire. 1998;149(11):1057–1064.

11. Willemse T. Atopic dermatitis - a review and reconsideration of diagnostic criteria. J Small Anim Pract. 1986;27:771–778.