CANINE ATOPIC DERMATITIS (AD)

Introduction

Canine atopic dermatitis (AD) is genetically predisposed inflammatory and pruritic allergic skin disease with characteristic clinical features associated with IgE antibodies most commonly directed against environmental allergens. Canine atopic-like dermatitis (ALD) describes an inflammatory and pruritic skin disease with clinical features identical to those seen in CAD; however, an IgE response to environmental or other allergens cannot be documented.

 Patients prone to IgE-mediated allergic reactions are said to be atopic. Atopic dermatitis is experienced by 3 % to 15% of the general canine population. Cutaneous exposure is believed to be the most important route of exposure; inhaled/ingested allergens may play some role in lesion development.

Signalment

Clinical signs typically begin at 6 months to 3 years of age. There is no sex predisposition. The following breeds were most commonly reported; West highland white terriers, Labrador and golden retrievers, German shepherd dogs, boxers, Dalmatian, Shar-peis, and French and English bulldogs. Depending on the allergens involved, the disease may be seasonal, non-seasonal or non-seasonal with seasonal flares.

Etiology and Pathogenesis

The environmental proteins to which the body overreacts or reacts in an abnormal manner are called allergens and include pollens, molds, dusts, danders, mites, and, in some cases, insects, chemicals, and foods.  

Canine atopic dermatitis (AD) is a dynamic disease and different mediators play a role at different times in the course of the reaction. The pathogenesis of atopy is mediated by numerous genetic as well as environmental factors (Fig 1). The disease process starts with percutaneous exposure and absorption of allergens through an epidermis that may have a defective barrier function.

1.       The naïve Langerhans cell captures and internalizes allergens. Allergens are then processed, packaged in major histocompatibility complex molecules on the Langerhans cell surface, and presented to naïve T-helper cells (Th0) cells in the draining lymph node. Specific cues from the microenvironment enable dendritic cells to activate T-helper cells and polarize them toward a Th2 phenotype.

2.       Th2 cells produce cytokines such as IL-4 and IL-13. These cytokines can stimulate B cells to become plasma cells that begin producing allergen-specific IgE.

3.       Activated Th2 cells migrate to the skin with the help of chemokines produced by various cells in the skin. Allergen specific IgEs also enter into the circulation and other tissues and bind to cells expressing high- and low-affinity Fcε receptors on their cell surface.

4.       Upon re-exposure to the same allergen, the epidermal Langerhans cell with cell surface–bound allergen-specific IgE efficiently binds the allergen and migrates to the dermis. These Langerhans cells then present the allergen to T-helper lymphocytes and continue to polarize them toward a Th2 phenotype. Additional Th2 cytokines such as IL-31 can be released and activate the sensory neuron to induce pruritus.

5.       Allergens can also cross-link allergen-specific IgE bound on the cell surface of dermal mast cells and stimulate the release of preformed inflammatory mediators such as histamine, serotonin, and substance P along with cytokines such as eosinophil chemotactic factor. Skin injury by scratching, microbial toxins from Staphylococcus sp and Malassezia sp, or environmental allergens activate keratinocytes and other innate immune cells to release pro-inflammatory cytokines (eg, IL-12) and chemokines that can polarize T-helper cells toward a Th1 phenotype, where they produce cytokines such as interferon (IFN)-γ.

6.      
In turn, IFN-γ promotes monocyte-macrophage cell activation. Activated keratinocytes, monocytes, and mast cells produce additional pro-inflammatory cytokines such as tumour necrosis factor (TNF)-α, upregulating the expression of P-selectin and E-selectin, on endothelial cells, thus recruiting more leukocytes from the blood. The epidermis thickens as does the stratum corneum; the barrier function worsens, allowing increased allergen penetration; and the cycle is perpetuated.

Clinical signs

The pruritus ranges from mild to severe. Erythematous macules, patches and micro papules (1-2 mm) consists the primary lesions of this disease. Excoriations, self-induced alopecia, lichenification (increased thickening), and scaling are the lesions that reflect chronic inflammation and self-trauma. As dogs with AD are predisposed to develop both superficial pyoderma and Malassezia dermatitis, lesions of bacterial folliculitis, exfoliative superficial pyoderma (epidermal collarettes) or seborrheic dermatitis can be present in addition to typical atopic skin lesions.  In most dogs with AD, the lesions are present in a characteristic distribution, and they are often bilaterally-symmetrical (Fig 2).

·       On the face, the lesions are visible on concave pinnae and the lips. The presence of periocular erythema, alopecia and lichenification reflects the presence of an associated allergic blepharo-conjunctivitis, a common occurrence.

·       On the trunk, lesions tend to affect areas of friction with poor hair coverage, such as the axillae, flanks, inguinal fold and lower abdomen. The ventral neck, perineum, perianal and ventral aspect of the tail are also commonly involved.

·       On the limbs, lesions clearly affect flexural aspects of the joints, such as those of the elbows, carpi, knees and hocks. Limb lesions are more medially than laterally distributed.

·       The feet most commonly harbour lesions, either in the dorsal interdigital space, or the ventral or dorsal metacarpi and metararsi. Between the footpads, lesions are often very edematous.

·       An otitis externa accompanies some 80% of the cases, and occasionally can be the main presenting sign. It commences by affecting the inner surface of the pinnae, auditory orifices and the vertical ear canals, but in longstanding cases the horizontal ear canals also become involved with a secondary infection involving bacteria and/or the yeast Malassezia.

·       Sneezing, reverse sneezing and rhinorrhoea in conjunction with cutaneous lesions likely herald the presence of associated allergic rhinitis. This can lead to profound facial pruritus in some dogs.  In contrary to the human atopic diseases, concurrent allergic asthma is a rare diagnosis made in dogs with AD.

Table 1. Additional body sites involved in canine AD in certain breeds

Breed	Location
Dalmatian French bulldogs German shepherd dog Boxer Shar-pei West Highland white terrier (WHWT)	Lips Eyelids, flexure surfaces Elbows, hind limbs, thorax Ears Thorax, flexure surfaces, dorso-lumbar area Dorso-lumbar area, lip, flexure surfaces

 

 Table 3. Key dermatological features for canine pruritic skin diseases

Alesional Pruritus	May be seen in the early stages of allergy or when seasonal disease begins. This finding of pruritus in areas with no lesions can occur in canine AD cases at any point in the disease process, especially in cases that have recurrences or come out of remission.
Primary skin lesions
Erythema	Can be seen with most of the above differentials, but lice and Cheyletiella do not usually cause erythema. Demodicosis is highly variable – the skin may or may not appear to be inflamed.
Papules	Seen with flea bites, scabies, Trombiculiasis, insect bite hypersensitivity, staphylococcal pyoderma, atopic dermatitis, cutaneous adverse food reaction, and contact dermatitis. Dogs with AD may have small non-crusted papules unless there are concurrent diseases.
Pustules	Most commonly associated with staphylococcal pyoderma
Secondary skin lesions
Epidermal collarettes	Most commonly associated with staphylococcal pyoderma
Crusting	Most commonly associated with secondary infections and excoriations
Salivary staining	Indicates excessive licking and often associated with Malassezia
Excoriations	Self-induced trauma from scratching due to severe pruritus
Alopecia	May be due to self-trauma or folliculitis (superficial pyoderma, demodicosis, and dermatophytosis)
Lichenification	Indicates chronic pruritus, inflammation and commonly associated with secondary infections
Hyperpigmentation	Indicates chronic pruritus. Allergies and Malassezia are the most common causes and result dark discoloration of the skin. Blue-grey pigmentation is seen with demodicosis in some cases.

 Diagnosis

The diagnosis of canine AD is made principally from a compatible signalment, suggestive history, and characteristic pruritus and clinical distribution.

International Committee for Allergic Diseases in Animals (ICADA) developed a set of practical guidelines that can be used to assist practitioners and researchers in the diagnosis of CAD. These guidelines provide an overview of the diagnosis of canine AD that involves three distinct, but complementary, approaches. These are:

1. Ruling out of other skin conditions with clinical signs that can resemble, or overlap with CAD. This is traditionally referred to as “the work-up”.

2. Detailed interpretation of the historical and clinical features of the condition. A new tool to assist with interpretation of these findings is the application of clinical criteria known as “Favrot’s criteria”.

3. Assessment of skin reactivity by Intradermal Testing (IDT) or detection of IgE by Allergen-Specific IgE Serology (ASIS) testing. This is traditionally referred to as “allergy testing”.

1.      Ruling out of other skin conditions with clinical signs that can resemble, or overlap with canine AD.

·       Consider the possibility of fleas (flea allergy dermatitis).

·       Consider the possibility of other ectoparasites (scabies, demodicosis, trombiculosis, otoacariasis, cheyeltiellosis).

·       Consider the possibility of Staphylococcal pyoderma and Malassezia dermatitis.

·       Consider the role of cutaneous adverse food reaction (CAFR). A strict elimination diet trial should be fed exclusively for a minimum of 8 weeks to achieve complete clinical remission in most cases.

·       Consider the possibility of contact dermatitis.

·       Consider the possibility of cutaneous/epitheliotropic lymphoma.

 

2.      Detailed interpretation of the historical and clinical features of canine AD

·       The initial clinical feature of canine AD is pruritus, which can include scratching, rubbing, chewing, excessive grooming or licking, scooting, and/or head shaking. Depending on the allergens involved, the pruritus may be seasonal (e.g., pollen) or non-seasonal (e.g., dust mites, food).

·       A new tool to assist with the interpretation of the clinical findings when confronted with a pruritic dog is application of clinical criteria known as “Favrot’s criteria” (Table 4). These include a set of criteria that have been developed from a large case series of confirmed cases of canine AD. The use of complex statistical analysis allowed a set of clinical features to be identified that had maximum association with canine AD. The analysis revealed two sets of criteria, which yield varying levels of sensitivity and specificity for the condition. Clinicians can use whichever set best serves their needs.

Table 2. Important differential diagnoses of pruritic skin diseases in dogs

Ectoparasitic skin diseases	Fleas Scabies (Sarcoptes scabie) Demodicosis Cheyletiellosis Otoacariasis (Otodectes cynotis) Trombiculiasis Nasal mites (Pneumonyssus caninum)
Microbial skin infections	Staphylococcal pyoderma Malassezia dermatitis
Allergic skin diseases	Flea allergy dermatitis Atopic dermatitis  Food intolerance/allergy Insect bite hypersensitivity Contact dermatitis
Neoplastic disease	Cutaneous lymphoma

 

Table 4. Favrot’s criteria

Use		Reliability
Set 1:	·       Use for clinical studies and adapt required criteria based on the goal of the study ·       If higher specificity is required, 6 criteria should be fulfilled (e.g., drug trails with potential side effects) ·       If higher sensitivity is required, 5 criteria should be fulfilled (e.g., epidemiological studies)	·       5 criteria: Sens. 85.4% Spec. 79.1%   ·       6 criteria: Sens. 77.2% Spec. 88.5%
1.       Age at onset <3 years 2.       Mainly indoor 3.       Corticosteroid responsive pruritus 4.       Chronic or recurrent yeast infections 5.       Affected front feet 6.       Affected ear pinnae 7.       Non-affected ear margins 8.       Non-affected dorso-lumbar area
Set 2:	·       Use to evaluate the probability of the diagnosis of  canine AD ·       5 criteria should be fulfilled ·       Do not use alone for the diagnosis of canine AD, and rule out resembling diseases	·       5 criteria: Sens. 85.4% Spec. 83%   ·       6 criteria: Sens. 42% Spec. 93.7%
1.       Age at onset <3 years 2.       Mainly indoor 3.       “Alesional” pruritus at onset 4.       Affected front feet 5.       Non-affected ear margins 6.       Non-affected dorso-lumbar area

 1.      Allergy testing

·       Once a clinical diagnosis of canine AD has been made several factors may play a role in the decision-making whether an allergy test is necessary or not. Severe clinical signs, duration of clinical signs for more than 3 months per year, and insufficient management with symptomatic therapy, due to side effects to the drugs used and/or poor owner compliance, justify in most cases allergy testing. These can be performed by IDT and ASIS. Both tests are not recommended as screening tests and should only be used to confirm the clinical diagnosis of canine AD. The results of these tests are also used to identify the offending allergen(s) in order to formulate an allergen-specific immunotherapy (ASIT).

·       Intradermal testing (IDT) 

The selection of test allergens should be made based on the prevalence of the allergens in a specific geographical region. Intradermal injections for IDT are most commonly performed on the lateral thorax, after the hair has been gently clipped and the injection sites marked (minimum 2 cm apart). Typically a volume of 0.05– 0.1 ml of each test concentration is injected intradermally and evaluated after 15–20 min. The reaction at each injection site will be compared between those of the positive (histamine phosphate) and negative (saline with phenol) controls. By convention, an allergen reaction is positive when the wheal formed is at least equal or greater than halfway between the negative and the positive control reaction. If the subjective evaluation is used, the positive control will assume a conventional grade of 4, whereas the negative control will be graded as 0. A reaction to an allergen is considered positive if it’s graded as 2 or greater.

·       Allergen specific IgE serology testing (ASIS)

These assays are used to detect specific IgE antibodies against a panel of allergens (e.g., pollen, mould, HDM and epidermal allergens) considered relevant for the patient.

Treatment

·       Allergen avoidance

If an allergen is known to trigger a flare, it is in the patient’s best interest to prevent further contact with such allergen. While this is the easiest to achieve in the case of flea, food and microbial allergens with flea control, diet restriction and antimicrobials, respectively, the prevention of contact with environmental allergens is difficult to impossible

·       Reactive anti-allergic therapy

Reactive therapy is the treatment of dogs with active skin lesions. It is best to continue the reactive therapy until a full and stable (e.g., two to four weeks) remission of signs before moving on to proactive therapy. For reactive therapy, several drugs have been shown to have a rapid (Glucocorticoids, Janus kinase inhibitors, Monoclonal antibodies) or slower effect (Calcineurin inhibitors).

1.      Glucocorticoids

Ø  Oral glucocorticoids (prednisolone) should be used at 0.5 mg/kg once- to twice- daily to induce remission of clinical signs of allergic pruritus in dogs.

Ø  After remission occurs, the dose of oral glucocorticoids should be tapered to the lowest dosage and frequency that maintains an absence of signs and minimises the risk of side effects over the long-term.

Ø  Topical glucocorticoids sprays, such as those containing triamcinolone or hydrocortisone aceponate, mometasone or methylprednisolone aceponate lotions can be used alone or in conjunction with oral glucocorticoids.

Ø  The major drawback to the use of systemic glucocorticoids in dogs is the potential adverse effects. Short-term use lead to polydipsia, polyphagia, panting, aggression and diarrhoea.

Ø  Prolonged use of glucocorticoids can lead to signs of iatrogenic hyperglucocorticism (muscle wastage, pot belly, hepatomegaly, fat redistribution, osteoporosis, calcinosis cutis, alopecia, poor wound healing, recurrent pyoderma, generalised demodicosis, comedones, pyelonephritis, cataracts, insulin resistant diabetes mellitus) and sudden withdrawal after prolonged therapy can lead to an Addisonian crisis (adrenal insufficiency).

 

2.      Janus kinase inhibitors (JAKinibs)

Ø  Oclacitinib administered at a dose of 0.4 to 0.6 mg/kg body weight, administered orally, twice daily for up to 14 days, and then administered once daily for maintenance therapy.

Ø  The drug is not approved for dogs under 12 months of age.

Ø  The most common adverse effects in the oclactinib is diarrhoea and vomiting.

Ø  The long-term administration of oclactinib administered once-daily appears to be relatively safe, whereas the long-term safety of other dosing regimens in not known.

3.      Monoclonal antibodies

Ø  Lokivetmab is a monoclonal antibody that specifically targets and neutralises canine IL-31, a key cytokine in the stimulation of pruritus in canine AD.

Ø  A single, subcutaneous injection at a minimum dose of 1 mg/kg typically provides a month of relief from pruritus. Repeat administration can be given monthly as needed in the individual patient.

Ø  Side effects are almost non-existent.

4.      Calcineurin inhibitors

Ø  Cyclosporin is a broad-spectrum oral immunosuppressant, which, at the dosage of 5 mg/kg/day until satisfactory control of clinical signs is achieved, which typically takes 4 to 6 weeks.

Ø  Thereafter, the dose required to maintain remission should be tapered by either decreasing the frequency from every day to every other day and then twice-weekly.

Ø  Adverse reactions in dogs receiving cyclosporine include gastrointestinal signs (vomiting, diarrhoea and reduced appetite) which are usually mild and transient. Gingival hyperplasia has been reported in dogs receiving cyclosporin.

Ø  Tacrolimus is a topical calcineurin inhibitor, which helps to reduce skin lesions.

·       Proactive therapy

Proactive (prophylactic) therapy is that of a dog whose signs are in remission to prevent their relapse.  Cyclosporin is one of the best drugs to use proactively in the long-term. Proactive topical glucocorticoid therapy (PTGT) (hydrocortisone aceponate) twice weekly, at the site of previously affected lesions to prevent their recurrence.

Ø  Allergen specific immunotherapy (ASIT) is the administration of increasing amounts of extracts of allergens to which the patient is hypersensitive to prevent or reduce flares of allergic diseases upon further contacts with the offending allergens. There is initially an induction phase with a slow increase in allergen dosing followed by a maintenance phase with less frequent injections of a higher concentration of extract. ASIT can be administered by several routes: subcutaneous, sublingual or intra-lymphatic. In dogs, ASIT is considered fairly safe and to, in average, result in a 60-70% of dogs having good-to-excellent results.

Ø  Antihistamines appear to have a limited benefit to control sings of AD, and they are probably more useful as antipruritic rather than to reduce skin lesions. Hydroxyzine (2 mg/kg twice daily) or cetirizine (1 to 2 mg/kg, once daily) are the antihistamines with proven pharmacodynamics effect in dogs.

·       Adjunctive therapy

Ø  Essential fatty acids (EFAs):

More recently, extensive research has brought to light the need to correct the skin barrier dysfunction seen in AD cases. It has been shown that in atopic dogs, there is an increase in the amount of transepidermal water loss (TEWL) in lesional and non-lesional skin. The oral intake of EFAs, especially those rich in omega-6 EFAs either as supplement or in enriched diets can help to restore the skin lipid barrier.

Ø  Shampoos

Non-irritant shampoos (e.g., Piroctone olamine) are an integral part of the management of AD.

Ø  Antimicrobial therapy

Antimicrobial therapy is needed in an atopic dog when a skin and/or ear infection with bacteria and/or yeast is diagnosed based on compatible clinical signs with or without supportive cytology or bacterial culture. The treatment of such infections usually consists of topical and/or systemic antimicrobials.

Conclusion

Canine AD is a chronic condition that can be difficult to manage and frustrating for owners and veterinarians alike. Prognosis for the long-term control of signs of AD is rather good. Treatment of this disease is clearly multifaceted and that interventions should be combined for a proven (or likely) optimal benefit. Furthermore, treatment should be tailored to each patient depending upon the stage of the disease, its severity and the distribution of lesions. Veterinarians should also remember to evaluate and then discuss with the pet owners the benefit of each recommended intervention, its side effects, its ease of administration, and its cost as a single or combined modality. Ultimately, the quality of life of both dogs and their owners, as well as the preferences of the latter, should be considered before a treatment plan is designed.

 

Case-study – Tsunami

Tsunami, a 2 year old, male, indie (non-descript) dog was presented with severe pruritus and lesions on face, limbs and trunk (Fig 3).  Skin scrapping examination was negative for mites. Wood’s lamp, cytology trichogram was negative for fungal infection.  An elimination diet trail (Hypoallergenic food) was conducted for 6 to 8 weeks with no result. Histopathological examination of skin biopsy (Fig 4) revealed hyperkeratosis, and mixed inflammatory infiltrate including mast cells in the sub-epidermal and perivascular compartment of the skin. There was response to initial glucocorticoid therapy and the dog was subsequently put on oral cyclosporin (5 mg/kg/day) for several weeks and then it was tapered down to twice weekly. The dog was given weekly bath with piroctone olamine shampoo. Topical tacrolimus (0.1%) ointment was used to control pruritus. Essential fatty acids (EFAs) were also used as adjunct therapy. Tsunami made excellent recovery in few weeks (Fig 5) after starting the cyclosporin therapy.

 

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