Clinical features of canine AD
In dogs, clinical signs of an environmental allergy mainly develop between 6 months and 3 years of age [
41]. Erythema is a primary lesion of canine AD; pruritus and inflammation can result in self-induced alopecia, excoriation and secondary infections with papules, pustules and crusts [
41,
42]. Axillae, ventral abdomen, distal extremities, inner pinnae and periocular, perioral and perianal regions are commonly affected [
42]. Otitis externa is present in half of the dogs with AD. Predilection sites differ from breed to breed [
43]. Even though dogs can have multiple target organs for hypersensitivities (including gut and respiratory) [
44], the contact with environmental allergens predominantly induces skin lesions in this species [
45]. There is no evidence for the progression of initially exclusive cutaneous lesions to respiratory signs and systemic hypersensitivities comparable to the “atopic march” in humans [
44]. In contrast to the cat, clinical examination in the dog frequently provides clues on the pathogenesis of the pruritus as to the presence of flea bite hypersensitivity versus environmentally-induced atopy or AFR. The former is characterized by pruritus focused on the dorsal lumbosacral area, ventral abdomen, tailbase and thighs.
Clinical features of feline atopy-like dermatitis
The manifestation of specific cutaneous reaction patterns [
46] can indicate an allergic primary cause in cats. These involve head and neck pruritus, miliary dermatitis characterised by small crusted papules, self-induced alopecia without any other clinical lesions and eosinophilic lesions such as eosinophilic indolent ulcers, eosinophilic granulomas and eosinophilic plaques [
32,
47]. In rare cases, untypical AD symptoms such as plasma-cell pododermatitis, seborrhoea, ceruminous otitis, facial erythema and exfoliative dermatitis were reported [
31,
48]. Additionally noncutaneous signs such as sneezing, coughing, conjunctivitis, diarrhoea or vomiting can be presented in affected cats [
32]. The disease onset can vary, but commonly it is under 3 years [
31,
32], whereas the mean age for AFR is slightly higher (approximately 4–5 years) with a range from 3 months to 11 years [
48]. In contrast to the dog, flea-bite hypersensitivity and environmentally induced and AFR look much more similar in the cat [
32].
Diagnosis
A differential diagnosis of AD is based on age of onset, breed and clinical signs. Other differential diagnoses such as ectoparasites and flea bite hypersensitivity must be ruled out by a consequent ectoparasite control. There is no single test differentiating the atopic from the non-atopic dog or cat [
49].
It is not possible to distinguish clinical signs of AD caused by perennial environmental allergens from AFR [
16,
50,
51]. Hence an elimination diet followed by a provocation with the original food should be performed in any dog or cat with non-seasonal AD [
52], particularly those with a long history of pruritus and/or gastrointestinal signs [
51,
53]. A diet length of 6–8 weeks is recommended, as 90% of the dogs with AFR show some improvement during this time period [
54]. Every food can potentially result in an AFR [
55]. The most common reported causative allergens for canine AFR are beef, dairy products, chicken, wheat, and lamb [
56]. However, soy, corn, egg, pork, fish and rice have also been reported as offending allergens [
56]. The food sources most frequently causing AFR in cats were beef, fish, and chicken [
58]. Wheat, corn, dairy products, lamb, egg, barley and rabbit were also reported as offending allergens in individual cats. The selection of appropriate protein and carbohydrate sources for an elimination diet can be challenging. It is important to use a protein and carbohydrate source, which the dog or cat has never received before [
52], thus a detailed food history needs to be obtained by the veterinarian. Multiple studies have shown that various commercial special diets with only one protein source on their label were contaminated and contained substances not listed on the label [
57‐
60]. Highly hydrolysed food is an alternative, but some dogs allergic to chicken also react to diets containing hydrolysed chicken protein [
61]. Therefore a home cooked diet by the owner is considered as diagnostic gold standard [
52], where instead of commercial dry or canned food the owner purchases one type of meat and one carbohydrate source and prepares those him-/herself for the pet. As cats are obligate carnivores, the use of a carbohydrate source is optional in the short term and indeed may reduce palatability. Currently there is no reliable alternative test for diagnosing food allergy [
62]. There is only poor correlation between IgE- and IgG-antibodies in the serum and clinical food reactions [
53,
63]. A patch test can be used for the selection of the elimination diet food source if the food history is unknown. This test has a poor positive predictability, but a high negative predictability [
53]. A lymphocyte proliferation test was able to detect a type IV hypersensitivity in the blood [
64‐
66] by measuring activated T-helper lymphocytes under food allergen stimulation with flow-cytometry [
66]. In 49 of 54 AFR dogs this test accurately provided positive reactions against one or more food allergens [
66], however this test is not commercially available at this time.
AD in animals is diagnosed by history, clinical examination and exclusion of all differential diagnoses. Positive reactions are frequently seen in healthy dogs on both intradermal tests [
67] and serum tests for allergen-specific IgE [
68]. The total serum IgE concentrations seem to have no clinical relevance in the dog [
44]. Once AD is diagnosed in an animal, testing can be used in combination with clinical historical information to choose which allergens should be selected for allergen immunotherapy. Serum tests for allergen-specific IgE and intradermal tests are equally useful and both are still performed with allergen extracts in animals, in contrast to component-resolved tests such as single molecule CAP testing or ImmunoCAP ISAC 112 microarray in human medicine [
45]. Prick puncture testing is not performed routinely in veterinary medicine, as intradermal testing is an established and safe diagnostic tool with a very low risk of adverse effects [
69].
General anti-inflammatory and anti-pruritic treatment
In severely affected dogs and cats, glucocorticoids, ciclosporin, oclacitinib or lokivetmab are used for symptomatic therapy due to their clinical efficacy and high success rates of 70–80% [
85].
Glucocorticoids are inexpensive, universally available and have been the mainstay of treatment for allergic pets for many years. However, the potentially severe adverse effects of oral and particularly injectable depot glucocorticoids such as polyuria and polydipsia, polyphagia, muscle atrophy, secondary skin infections, calcinosis cutis and others have led to the development of alternative drugs for dogs and cats.
Ciclosporin, a calcineurin inhibitor, is highly effective in dogs and cats with comparable results to glucocorticoids [
86‐
88]. The initial daily dosage can be reduced in the majority of animals to every other day or twice weekly [
86,
87]. Mild gastrointestinal symptoms (e.g. diarrhoea and vomiting) frequently occur at the beginning of treatment but usually resolve during continued administration [
89]. Hirsutism, gingival hyperplasia and hyperplastic dermatitis are reported adverse effects which typically resolve with dose reduction or discontinuation [
87]. Sporadic case reports exist of immunologically naive cats newly infected with
Toxoplasma gondii, developing systemic and even fatal clinical signs [
90,
91]. It is recommended to evaluate anti-toxoplasma antibodies in outdoor cats and cats fed raw meat prior to initiating cyclosporine therapy.
Oclacitinib is a selective inhibitor of janus kinase 1. Janus kinase 1 is involved in the signaling pathways of the receptors for IL-2, IL-4, IL-6, IL-13 and IL-31 [
92], and thus aims at blocking the Th2 pathway. It is administered to dogs at a dose of 0.4–0.6 mg/kg twice daily for 2 weeks and then daily at that dose is reported to be as effective as glucocorticoids [
93,
94]. In comparison to cyclosporine, oclacitinib has a more rapid effect and gastrointestinal adverse effects are less frequently observed [
95]. Skin infections and histiocytomas were reported with increased frequency in dogs on longer term oclacitinib therapy [
93]. Oclacitinib given to a small number of cats with atopy-like dermatitis over a 4 week period was effective [
96], however the dose required was higher than for dogs, the period of monitoring was short and both more and larger studies are needed before it can be recommended as standard therapy.
Different
antihistamines are associated anecdotally with individual responses, therefore a trial therapy with various antihistamines over 7–14 days is recommended [
97,
98]. Histamine binds to four receptor subtypes (H1to H4) which are expressed in different tissues [
99]. Its interaction with the high-affinity H1 receptor is known to cause cutaneous vasodilatation, oedema, and wheal formation. Histamine can also attract effector cells such as eosinophils to the region of inflammation [
99]. Antihistamines targeting the cutaneous H1 receptors block the binding of histamine and are used most frequently in order to reduce the pruritus in atopic dogs [
100]. Antihistamines binding to the H4 receptor showed an anti-inflammatory and anti-pruritic effect in mice [
101,
102]. However, they did not prevent the development of acute skin lesions in a canine atopic model [
103]. A double blinded, placebo-controlled, cross-over study evaluated the efficacy of dimetindene and a combination of hydroxyzine and chlorpheniramine in 19 atopic dogs and concluded that in both groups a limited, but significant improvement on pruritus was achieved, nevertheless other drugs might additionally be needed [
104]. Many owners consider antihistamines useful therapeutic agents for their pets’ allergy [
105]. The recommended dosage of antihistamines is much higher in cats and dogs than in humans. Dogs can rapidly metabolise hydroxyzine to cetirizine and need twice daily hydroxyzine orally at 2.0 mg/kg [
99]. In one study a positive effect of antihistamines, mainly loratadine and cetirizine, was shown in 67% of 31 atopic cats [
33]. In contrast, in another study, cats with allergic dermatitis treated with cetirizine hydrochloride showed no significant differences in lesion- and pruritus-scores to those treated with placebo [
106].
A future non-specific treatment alternative might be the subcutaneous injection of cytosine-phosphate guanine
oligodeoxynucleotides bound to gelatine nanoparticles (CpG GNPs). This therapy resulted in decreased lesions and pruritus in ≥ 50% of atopic dogs, similar to what is seen with AIT and the mRNA expression of IL-4 was also decreased in those dogs [
107]. However, this treatment is currently not commercially available.
Due to their hair coat and compliance issues,
topical treatment of dogs and cats can be difficult for owners and therefore it is less frequently used than in humans [
44]. Topical glucocorticoid ointments can be used for localised skin lesions in sparsely haired areas, but prolonged application may result in skin atrophy [
98]. Topical hydrocortisone aceponate was effective for canine AD [
108,
109] and feline atopy-like dermatitis [
110]. Topical calcineurin inhibitors such as tacrolimus have been used successfully in localized lesions of canine AD [
111,
112]. Atopic dogs may benefit from shampoo therapy [
113,
114].
Adding
dietary supplementations such as essential fatty acids (EFA), probiotics or vitamins can have a positive benefit for atopic animals. EFA are used to treat AD in cats [
115] and dogs [
116]. Oral EFA can improve the coat quality, strengthen the skin barrier and reduce the transepidermal water loss [
117]. Moreover EFA can lower the amount of glucocorticoids and cyclosporine needed to control clinical signs of canine AD [
118,
119].
Probiotics are microorganisms that are claimed to provide health benefits when consumed [
120,
121]. Their mechanism is not completely elucidated, but may involve binding Toll-like receptors and downregulate the allergic predominately TH2-mediated response [
122,
123].
Lactobacillus paracasei K71 given orally to atopic dogs led only to a slight improvement of lesion- and pruritus-score [
124]. However, the medication score was reduced significantly indicating a potential benefit as a complementary therapy [
124].
Lactobacillus rhamnosus GG given to puppies led to a reduction of immunologic indicators of AD, even though no significant clinical improvement was observed [
125].
In human studies a positive impact of
cholecalciferol on AD was detected [
126‐
128]. Similarly, systemic cholecalciferol reduced pruritus and lesion scores in dogs with AD [
129].