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.     

Masitinib for the treatment of canine atopic dermatitis: a pilot study

There is an on-going need to identify medications suitable for the long-term treatment of canine atopic dermatitis (CAD). Masitinib mesilate is a potent and selective tyrosine kinase inhibitor of the c-KIT receptor. A strong relationship exists between the SCF/c-KIT pathway and pathogenesis of CAD, suggesting that masitinib may potentially fulfil the above role. This study reports on an uncontrolled pilot study of masitinib in CAD. Masitinib was administered orally to 11 dogs at a mean dose of 11.0 ± 1.83 mg/kg/day (free base) for 28 days. Treatment response was assessed by evolution of clinical appearance according to a modified version of the Canine Atopic Dermatitis Extent and Severity Index (mCADESI), pruritus scale and surface area of lesions. Masitinib improved CAD with a mean reduction in mCADESI of 50.7 ± 29.8% (95% C.I. = 29.4–72.0; p = 0.0004) at day 28 relative to baseline, with 8/10, 8/10 and 4/10 dogs showing improvement of ≥33%, ≥40% and ≥50%, respectively. Improvement was further evidenced by a decrease in pruritus score and the surface area of lesions. No serious or severe adverse events occurred during this trial, although 6/11 dogs presented with mild to moderate treatment related adverse events. There is sufficient compelling evidence to warrant further investigation.     

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.     

A prospective study on the clinical features of chronic canine atopic dermatitis and its diagnosis

Canine atopic dermatitis (CAD) is a multifaceted disease associated with exposure to various offending agents such as environmental and food allergens. The diagnosis of this condition is difficult because none of the typical signs are pathognomonic. Sets of criteria have been proposed but are mainly used to include dogs in clinical studies. The goals of the present study were to characterize the clinical features and signs of a large population of dogs with CAD, to identify which of these characteristics could be different in food-induced atopic dermatitis (FIAD) and non–food-induced atopic dermatitis (NFIAD) and to develop criteria for the diagnosis of this condition. Using simulated annealing, selected criteria were tested on a large and geographically widespread population of pruritic dogs. The study first described the signalment, history and clinical features of a large population of CAD dogs, compared FIAD and NFIAD dogs and confirmed that both conditions are clinically indistinguishable. Correlations of numerous clinical features with the diagnosis of CAD are subsequently calculated, and two sets of criteria associated with sensitivity and specificity ranging from 80% to 85% and from 79% to 85%, respectively, are proposed. It is finally demonstrated that these new sets of criteria provide better sensitivity and specificity, when compared to Willemse and Prélaud criteria. These criteria can be applied to both FIAD and NFIAD dogs.     

A double-blinded placebo-controlled evaluation of adipose-derived mesenchymal stem cells in treatment of canine atopic dermatitis

Mesenchymal stem cells (MSCs) have emerged as a new therapy for various immune-mediated inflammatory diseases. In this study we perform the first double-blinded, placebo-controlled evaluation of the efficacy of adipose-derived allogenic canine MSCs for the treatment of canine atopic dermatitis (cAD). Enrolled canine patients were randomly divided into placebo (PBS saline), low-dose (5?×?10⁵ cells/kg), and high-dose (5?×?10⁶ cells/kg) treatment groups. Each patient received three subcutaneous MSCs treatments or PBS saline at four-week intervals with injections at five sites. Patients were monitored by physical exams, pruritus visual analog scales (PVAS) signed by the primary caretaker, canine atopic dermatitis extent and severity index-4 (CADESI-4) scores by two veterinarians, and complete blood count and serum chemistry analysis along with laboratory analysis for potential biomarkers. Patients were kept off any immune-modulating drugs during the study period, and oral antibiotics and topicals were used for managing pruritus and secondary infections. The PVAS scores and the serum miR-483 levels were significantly lower in the high dose group compared to the placebo group at day90 post first-treatment. The CADESI-4 scores of the high dose group also showed downward trends. No severe adverse effects were observed in any patient in this study. The high dose MSC treatment is efficacious in alleviating the clinical signs of cAD until 30 days after the last subcutaneous administration of MSCs, and miRNA-483 may be a reliable prognostic biomarker for cAD. The MSCs efficacy and potential biomarkers should be further explored by a larger scale clinical trial.

     

FC-38 Efficacy of conjugated linoleic acid and black currant seed oil in the treatment of canine atopic dermatitis: a double-blinded, randomized, placebo-controlled study

The purpose of this study was to evaluate a combination of immunostimulatory bacterial DNA sequences and allergen-specific immunotherapy for the treatment of canine atopic dermatitis. Seven dogs with nonseasonal atopic dermatitis diagnosed by history, clinical signs and exclusion of differential diagnoses were included. All dogs had been on allergen-specific immunotherapy for at least 12 months with incomplete responses, were on additional antipruritic therapy and showed residual pruritus. Pruritus was marked by the owner on a visual analogue scale, lesions were determined by a clinician using the Canine Atopic Dermatitis Extent and Severity Index (CADESI), and concurrent medications were recorded before entering the study and after 14 weeks of treatment. Peripheral blood mononuclear cells were isolated and cultured; canine cytokine message for IFNγ, IL-4, TNF and IL-10 was quantitated using RT-PCR. A mixture of allergen extract and liposome-DNA complexes was injected intradermally at the beginning of the study and after 2, 4, 6, 10 and 14 weeks. CADESI, pruritus and medication scores, and cytokine messages at the beginning and end of the study were compared with a paired t -test. There were significant improvements in pruritus scores ( P  = 0.0277). Reductions in medication scores and CADESI were not statistically significant. IL-4 production decreased significantly ( P  = 0.0428); decreases in other cytokines were not significant. Although the number of dogs in this pilot study was small, the results warrant further investigation of a combination of immunostimulatory bacterial DNA sequences and allergen-specific immunotherapy for the treatment of canine atopic dermatitis.
Funding: Self-funded.     

Tolerability and clinical efficacy of oral immunotherapy with house dust mites in a model of canine atopic dermatitis: a pilot study

Atopic dermatitis (AD) is a chronic, life‐long disease. In humans, immunotherapy (IT) is the only treatment that can alter the course of AD. Oral IT is appealing owing to the ease of administration and the potential for increased compliance. The purposes of this study were to investigate the tolerability, clinical efficacy and effects on allergen‐specific IgE of oral IT using a canine AD model. Thirteen atopic beagles sensitized to house dust mites (HDMs) were randomly divided into two groups. One group received daily oral doses of HDMs while the other group received vehicle only for 7 months. The investigator evaluating the dogs was blinded to the allocation of treatments. Prior to and after 2 and 7 months of IT, dogs were challenged daily with HDMs for 3 days concurrently, and clinical signs were scored using a modified Canine Atopic Dermatitis Extent and Severity Index (CADESI). Prior to and at completion of oral IT, serum was collected for measurement of allergen‐specific IgE. Oral IT was well tolerated, and no adverse effects were noted. Analysis of variance showed no significant effect of time, group and group × time interaction for CADESI scores. In addition, there were no significant differences in allergen‐specific IgE levels. In conclusion, it appears that oral administration of HDMs is well tolerated in these atopic beagles but that this protocol was not sufficient to induce clinical improvement. Further, longer‐term studies will be necessary to explore the potential of oral IT in veterinary medicine.     

Investigation on the clinical efficacy and safety of 0.1% tacrolimus ointment (Protopic) in canine atopic dermatitis: a randomized, double-blinded, placebo-controlled, cross-over study

Topical tacrolimus is successfully used in people with atopic dermatitis. Preliminary studies in dogs with atopic dermatitis using tacrolimus in a compounded lotion formulation indicated that tacrolimus significantly decreased erythema and pruritus according to investigator, but no significant improvement was reported by the dog owners. The objectives of this study were to evaluate the clinical efficacy and safety of the commercially available 0.1% tacrolimus ointment (Protopic) in dogs with atopic dermatitis. The study was designed as a double-blinded, placebo-controlled, cross-over study. Selected dogs were allocated to either tacrolimus or placebo for 4 weeks. After 4 weeks there was a wash-out period of 2 weeks and treatments were switched. Twelve dogs completed the study. Clinical signs were scored. Blood samples were collected for complete blood count, chemistry panels and tacrolimus levels at week 0 and 4 of each treatment. Tacrolimus ointment significantly decreased severity of symptoms for both owners and investigators at the end of the trial. When the same dogs received the placebo, there were no differences between week 0 and week 4 scores. Dogs with localized disease responded better than dogs with generalized disease. Tacrolimus was detected in the blood of animals receiving the active ingredient. Levels were below the level of toxicity and no adverse effects were reported in any of the dogs. No changes in complete blood count and chemistry parameters were detected between groups or within groups. In conclusion, tacrolimus appears to be a safe alternative treatment in dogs with atopic dermatitis, especially in those with localized disease.     

Tepoxalin reduces pruritus and modified CADESI-01 scores in dogs with atopic dermatitis: a prospective, randomized, double-blinded, placebo-controlled, cross-over study

Thirty dogs with atopic dermatitis were given tepoxalin (Zubrin®, Intervet/Schering-Plough Animal Health, Boxmeer, the Netherlands) or placebo once daily for 4 weeks, followed by a wash-out period of 1 week before reversing the treatments. Pruritus was scored by the owners using the Edinburgh Pruritus Scale and one investigator employed a modification of the Canine Atopic Dermatitis Extent and Severity Index-01 (mCADESI-01) to score the physical lesions. After administration of tepoxalin there was a ≥ 50% reduction in pruritus and mCADESI-01 scores in 36% and 25% of the dogs, respectively, whereas following administration of the placebo there was a ≥ 50% reduction in pruritus and mCADESI-01 scores in only 25% and 16% of the dogs, respectively. Analysis of pooled data indicated that tepoxalin resulted in a significant reduction in pruritus ( P  = 0.012) and mCADESI-01 ( P  = 0.002) scores but there was no significant change after placebo. The median pruritus scores before and after tepoxalin were 2 (range 1–5) and 1 (range 0–5), respectively, and before and after placebo were 2 (range 0–4) and 2 (range 0–4), respectively. The median mCADESI scores before and after tepoxalin were 23 (range 0–68) and 16 (range 0–72), respectively, and before and after placebo were 18 (range 3–79) and 24 (range 0–65), respectively. At the dose used in this study (10.0–19.1 mg kg⁻¹), tepoxalin was well-tolerated and no adverse effects were noted.     

Management of canine atopic dermatitis using the plant extract PYM00217: a randomized, double-blind, placebo-controlled clinical study

This study evaluated PYM00217, a proprietary blend of plant extracts, in the management of canine atopic dermatitis (AD). One hundred and twenty dogs were diagnosed with perennial AD on the basis of history, clinical signs, a positive test for perennial allergens and elimination of other dermatoses. Exclusion criteria included antimicrobials within 7 days, antihistamines within 14 days, oral/topical glucocorticoids or ciclosporin within 28 days, and parenteral glucocorticoids, essential fatty acids or immunotherapy within 56 days. Flea control, shampoos and ear cleaners were permitted. Dogs with a minimum canine atopic dermatitis extent and severity index (CADESI) of 25 were randomly allocated to receive PYM00217 (100, 200 or 400 mg kg-1 day-1) or placebo for 12 weeks. The mean reductions in CADESI (intention-to-treat population) were 3.9% (placebo; n=29), 4.4% (100 mg kg-1 day-1; n=30), 23.4% (200 mg kg-1 day-1; n=29) and 8.5% (400 mg kg-1 day-1; n=29). The reduction in the 200 mg kg-1 day-1 group was significant (P<0.01). For dogs with a baseline CADESI>or=50, the mean changes were +10.6% (placebo; n=12), +0.6% (100 mg kg-1 day-1; n=14), -29.3% (200 mg kg-1 day-1; n=14) and -3.4% (400 mg kg-1 day-1; n=15). The 200 mg kg-1 day-1 dose was significantly more effective than placebo (P=0.038). No serious adverse effects were reported. Minor adverse effects seen in 10% (placebo and 100 mg kg-1 day-1), 24% (200 mg kg-1 day-1) and 42% (400 mg kg-1 day-1) of cases were mainly minor gastrointestinal disorders and only five cases required cessation of dosing. Two dogs (one in each of the 100 mg kg-1 day-1 and 200 mg kg-1 day-1 groups) refused to eat the medicated food. In conclusion, PYM00217 at 200 mg kg-1 appears to be an effective, palatable and well-tolerated treatment for canine AD.     

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.     

The effects of capsaicin topical therapy in dogs with atopic dermatitis: a randomized,double-blinded,placebo-controlled,cross-over clinical trial

Abstract The efficacy of twice daily topical application of capsaicin (0.025%) for the management of pruritus in dogs with atopic dermatitis (AD) was evaluated in double-blinded, placebo-controlled study. Twelve dogs with AD were randomly assigned to either 0.025% capsaicin or vehicle lotion applied twice daily for 6 weeks. After a 4-week wash-out period, treatments were switched. Significant improvement was reported by owners ( P  = 0.0006), but not by investigators. Owners noted temporary worsening of pruritus after the first week of capsaicin therapy. Overall capsaicin was well tolerated. Substance P (SP) concentrations in the skin did not correlate with the severity of the pruritus and did not change significantly over time and between treatments. Lesional skin had less SP than nonlesional skin ( P  = 0.03). These observations suggest that topical capsaicin should be further evaluated as an adjunctive antipruritic agent in dogs with AD.