The future of immunotherapy for canine atopic dermatitis: a review

Allergen specific immunotherapy (ASIT) is a foundation treatment for canine atopic dermatitis (CAD), though few critical studies have documented its effectiveness as a disease‐modifying treatment in dogs. The mechanisms by which ASIT works in dogs have not been elucidated, although they are likely to parallel those known for humans. Current ASIT approaches in CAD focus on either subcutaneous or sublingual administration. Greater knowledge of major allergens in dogs, ideal dosage regimes and details of allergen admixture are likely to lead to better efficacy in CAD. Evaluation of biomarkers for successful therapy may also be of benefit. Potentially important advances in human medicine, that have yet to be explored in dogs, include use of modified allergen preparations such as allergoids, recombinant major allergens or allergen peptides; modification with adjuvants; or packaging of the above in virus‐like particles. Co‐administration of immunomodulators such as CpG oligodeoxynucleotides or specific monoclonal antibodies might direct the immune response in the desired direction while calming the “cytokine storm” of active disease. Initial trials of alternative routes of administration such as intralymphatic immunotherapy have yielded exciting results in humans, and continuing study in dogs is underway. Progress in ASIT of human food allergy may provide clues that will assist with improved diagnosis and patient management of CAD. Importantly, further study must be undertaken to clarify the conditions under which ASIT is a valuable treatment modality for dogs.     

Breed-associated phenotypes in canine atopic dermatitis

Canine atopic dermatitis is a multifaceted disease, whose clinical presentation may be affected by numerous factors, including the genetic background of the animal, the environment, the offending allergens and flare factors. In particular, breed-associated differences have often been mentioned but never defined precisely. Using a large data set of atopic dogs, we document in this study the clinical presentation of nine often-affected breeds and demonstrate the existence of substantial differences between the clinical phenotype of each breed and the whole population. Some of the differences may be due to genetic differences while others are most likely to be associated with variations in environmental factors.     

Oxidative stress markers in canine atopic dermatitis

There are no data in the veterinary literature relating to oxidative stress in canine atopic dermatitis (CAD). The study aimed to determine levels of oxidative stress markers, plasma malondialdehyde (MDA), total antioxidant capacity (TAC), whole blood glutathione peroxidase (GPX) and erythrocyte superoxide dismutase (SOD), in 15 CAD patients and 17 healthy dogs. A correlation between CADESI (Canine Atopic Dermatitis Extent and Severity Index) score and MDA was also determined. Significantly higher plasma MDA levels were found in patients than in healthy dogs. The significant, highly positive correlation determined between CADESI score and MDA in the patient group indicates an association between the severity of CAD and the extent of oxidative damage to membrane lipids. There were no significant differences in TAC, GPX and SOD between patients and healthy dogs. Our findings suggest that oxidative stress with increased lipid peroxidation could be involved in the pathogenesis of atopic dermatitis in dogs.     

The ACVD task force on canine atopic dermatitis (XXIV): allergen-specific immunotherapy.

Allergen-specific immunotherapy (ASIT) has been used for years to treat dogs with atopic dermatitis (AD) and humans with atopic diseases. The efficacy of ASIT has been well documented for humans with respiratory atopic diseases and stinging insect allergy, but its effectiveness seems more controversial for patients with AD. In spite of insufficient evidence derived from randomized controlled trials, multiple open studies and a large body of clinical observations suggest that ASIT is effective in controlling the clinical signs of dogs with AD. As a result of the scarcity of evidence from controlled trials, the true efficacy of ASIT, and the optimal protocols for allergen dose and frequency of injection are currently unknown. Allergen-specific immunotherapy nevertheless may be included in the treatment of canine AD because of its potential advantages and limited disadvantages compared to other forms of therapy. There is no evidence, however, for the preference of any specific treatment protocol. The predictive value of historical, clinical and immunologic features related to the efficacy of ASIT in dogs with AD are discussed in this paper. Adverse reactions, and the requirements for monitoring of patients receiving ASIT, then are reviewed and detailed. Finally, this review highlights aspects of ASIT where further research and controlled studies are needed.     

Prevalence and features of canine atopic dermatitis in Hungary

Medical records of 600 dogs diagnosed with atopic dermatitis were reviewed and evaluated with reference to history, geographical distribution, breed predilection, clinical signs and positive reactions to allergens as determined by intradermal skin testing (IDT) manufactured by Artuvetrin Laboratories. In 66.6% of dogs, the age of onset of atopic dermatitis was between 4 months and 3 years. Dogs living in the garden suburb of Budapest were more sensitive to house dust mites, fleas and moulds, and dogs from the western part of Hungary were more sensitive to weeds than to other allergens (p < 0.01). Positive reactions were most common to Dermatophagoides farinae followed by human dander. The breed distribution found in the present study was consistent with that reported in the literature, except for the breeds Hungarian Vizsla, Pumi, French bulldog, Doberman Pinscher and Bobtail which were over-represented among atopic dogs compared to the breed distribution of the general dog population of a large city in Hungary. Breeds with verified adverse reaction to food were Cocker spaniels, French bulldogs, Bullmastiffs, Bull terriers, St. Bernards, Tervurens, West Highland White terriers and American Staffordshire terriers (p < 0.05). The clinical signs of atopic dermatitis and their occurrence are in accordance with the data described in the literature.     

Advances in our understanding of canine atopic dermatitis

Canine atopic dermatitis (cAD) is a genetically inherited clinical syndrome that encompasses a diversity of mechanisms and can have a variety of triggers. Development of clinical disease is the result of genetic factors and environmental conditions, which shape the resulting immunological response. Clinical disease becomes evident once a threshold of inflammatory response is achieved. Skin barrier impairment plays a role in promoting cutaneous dysbiosis and increased allergen penetration. Keratinocytes shape the response of dendritic cells and subsequent lymphocytic response. Thymic stromal lymphopoietin is one of the links between the damaged skin barrier and the modulation of a T-helper (Th)2 response. It is still unclear whether mutations in skin barrier genes exist in atopic dogs, as they do in humans, or whether the observed alterations are purely secondary to inflammation. A dysregulated immune response with increased Th2, Th17 and CD4+ CD25+ regulatory T cells has been reported. A variety of cytokines [interleukin(IL)-31, IL-34, Macrophage migration inhibitory factor] are proposed as potential biomarkers and treatment targets because they are increased in the serum of atopic dogs when compared to controls, although a correlation between serum levels of these factors and severity of disease is not always present. The main issue with many published studies is that atopic dogs are always only compared to normal controls. Thus, it is unclear whether the changes that we find are truly a signature of cAD or merely a manifestation of nonspecific broad inflammatory responses. Studies considering comparison with other inflammatory diseases different from cAD are urgently needed to correctly identify what is specific to this complicated syndrome.     

A prospective study on canine atopic dermatitis and food-induced allergic dermatitis in Switzerland

Canine atopic dermatitis sensu stricto and food-induced allergic dermatitis are common canine skin conditions, which are often considered clinically undistinguishable. Several attempts have been made to describe populations of atopic dogs and determine breed predisposition but the results were often biased by the use of hospital populations as control group. The present study aims to describe a population of Swiss atopic and food-allergic dogs and to compare it with a data set representing more than 85% of all Swiss dogs. The study, which was carried out during 1 year in several practices and teaching hospital in Switzerland, describes a group of 259 allergic dogs, determines breed predisposition for atopic dermatitis and food-induced allergic dermatitis, compares the clinical signs and features of both conditions, and outlines the clinical picture of five frequently affected breeds.     

The ACVD task force on canine atopic dermatitis (III): the role of antibodies in canine atopic dermatitis.

Although an important pathogenic role for IgE is established in the case of allergic asthma and rhinitis in man, its role in atopic dermatitis is less clear. There are many studies where allergists and immunologists have provided evidence in favour of such a role, whereas dermatologists are less than convinced.In dogs, however, there is an abundance of clinical evidence implying that atopic dermatitis is antigen driven, and recent studies suggest that there may be a role for IgE, not only in the effector pathway, but also in antigen capture. Although an IgG response often accompanies an IgE response in dogs with atopic dermatitis, there is little evidence in support of a pathogenic role in respect of the former isotype.     

Recent developments in canine atopic dermatitis: a review

Atopic dermatitis (AD) is a genetically predisposed inflammatory and pruritic allergic skin disease with characteristic clinical features. New results on the pathogenesis and therapeutic aspects are discussed in this review. IgE-mediated hypersensitivity may be involved in the largest subset of atopic patients, yet there is another subset for which such involvement cannot be documented. Alterations in epidermal barrier function, priming of cutaneous antigen-presenting cells with IgE, intrinsic keratinocyte defects, and development of autoimmunity are also factors that contribute to the primary disease. Polymorphisms in regions of the genome that are of key importance to the inflammatory response contribute to the patient's clinical picture. Secondary infections, especially with Staphylococcus and yeast organisms, strongly modify or augment the inflammatory response, which changes over time. After the treatment of secondary infections and skin inflammation the avoidance of causal allergens would prevent relapse. Another causative therapy is the variously effective allergen-specific immunotherapy. The newest treatments for canine AD (cyclosporin A and tacrolimus) are highly effective at suppressing the allergic response and comparable to treatment with glucocorticoids. Canine AD presents a substantial diagnostic and therapeutic challenge over a patient's lifetime, and no single treatment is universally effective.     

Serum antibodies to Malassezia yeasts in canine atopic dermatitis

Significant numbers of humans with atopic dermatitis develop Malassezia-specific IgE. Immediate skin-test reactivity to Malassezia has been demonstrated in atopic dogs. The aim of this study was to compare the serum IgG and IgE response to Malassezia in atopic dogs with and without clinical evidence of Malassezia dermatitis and/or otitis, nonatopic dogs with clinical evidence of Malassezia dermatitis and/or otitis and healthy dogs. Cytology was used to diagnose clinically significant Malassezia dermatitis and otitis. Contact plate cultures confirmed the validity of this technique. Reproducible enzyme-linked immunosorbent assays for Malassezia-specific IgG and IgE in canine serum were established. Atopic dogs had significantly higher serum IgG and IgE levels than either healthy dogs or nonatopic dogs with clinical evidence of Malassezia dermatitis and/or otitis. There was no significant difference in IgG and IgE levels between atopic dogs with and without clinical evidence of Malassezia dermatitis and/or otitis. The implications of these findings in the pathogenesis and management of canine atopic dermatitis are discussed.     

Expression of thymic stromal lymphopoietin in canine atopic dermatitis

Background – In humans, thymic stromal lymphopoietin (TSLP) plays a central role in the development of allergic inflammation, such as atopic dermatitis (AD), but it is unknown whether it is involved in the pathogenesis of canine AD (CAD). Hypothesis/Objectives – Our aim was to characterize canine TSLP and to assess its expression in CAD. Methods – Canine TSLP was identified based on sequence homology with human TSLP and the complementary DNA (cDNA) cloned by RT‐PCR. Real‐time quantitative RT‐PCR was established to assess the expression of canine TSLP in cultured canine keratinocytes and in skin biopsy specimens from lesional and nonlesional skin of 12 dogs with CAD and eight healthy control dogs. Results – Partial canine TSLP cDNA was cloned and characterized. It contained four exons that shared 70 and 73% nucleotide identity with human and equine TSLP, respectively, encoding the signal peptide and full‐length secreted protein. We found significantly increased TSLP expression in lesional and nonlesional skin of dogs with CAD compared with healthy control dogs (P < 0.05), whereas no difference was measured between lesional and nonlesional samples. In cultured primary canine keratinocytes, we found increased TSLP expression after stimulation with house dust mite allergen extract or Toll‐like receptor ligands lipopolysaccharide and poly I:C. Conclusions and clinical importance – Increased TSLP expression in the skin of dogs with CAD supports an involvement of TSLP in the pathogenesis of CAD similar to that in humans. Further studies should elucidate the function and therapeutic potential of TSLP in CAD.     

Inverse association between endotoxin exposure and canine atopic dermatitis

The development of canine atopic dermatitis (CAD) may be related to exposure to mite allergens, bacterial endotoxin and/or fungal glucans. In this study, indoor exposure levels of house dust mite allergens, endotoxins and fungal glucans were measured to determine their possible association with CAD. A case-control study including adult Labrador retrievers with (n=28) and without (controls; n=65) CAD was conducted. Dust samples were collected from the living room floor and the bedding and coat of the dog and these were analyzed for house dust mite allergens Der p1 and Der f1, endotoxin and (1→3)-β-d-glucan levels. Dog owners were also required to return a questionnaire regarding their home characteristics. The endotoxin exposure level in the coats of dogs was significantly inversely associated with CAD (odds ratio 0.38; 95% confidence interval 0.15-0.97; P<0.05). No significant difference was found in exposure levels to house dust mite allergens and fungal glucans. The results indicated that endotoxin exposure is inversely associated with CAD, suggesting a protective effect of high indoor endotoxin exposure towards the development of the condition.     

Results of allergen-specific immunotherapy in 117 dogs with atopic dermatitis

The success of the treatment of 117 dogs with atopic dermatitis with allergen-specific immunotherapy for up to 48 months was assessed. An excellent response (remission with exclusive immunotherapy) was recorded in 18 of the dogs, a good response (more than 50 per cent reduction in medication and improvement of clinical signs) was recorded in 57, a moderate response was recorded in 24 and a poor response in 18. The mould antigens in the allergen extract were stored in a separate vial before administration and the success rate of the immunotherapy including mould antigens was much higher than in an earlier study in which mould and pollen antigens had been stored in one vial. The success rate was not affected significantly by the age of the dogs when the disease developed, or by their age or the period for which they had shown clinical signs when the treatment began; it was also unaffected by whether pollens, moulds or dust mites were used as antigens, or by whether the offending allergens had been identified by intradermal testing or by serum testing for allergen-specific immunoglobulin E.