Ralf S. Mueller, DACVD, FACVSc, DECVD
Center for Clinical Veterinary Medicine, Ludwig Maximilian University, Munich, Germany
This lecture will summarize the results of therapeutic trials using glucocorticoids, calcineurin inhibitors, oclacitinib, antihistamines, fatty acids, leukotriene and phosphodiesterase inhibitors, prostaglandin analogues, allergen-specific immunotherapy (ASIT) and topical therapy for canine atopic dermatitis.
There is only one RCT evaluating topical 0.015% triamcinolone acetonide. After 4 weeks, clinician-assessed overall scores and owner-assessed pruritus scores decreased by 67% and significantly more than with placebo treatment. Oral glucocorticoids typically were evaluated as standard-of-care controls in RCTs for comparison with other interventions and methylprednisolone, prednisone and prednisolone at 0.4–1 mg/kg/day were most commonly used.1 At the end of 4–16 weeks of treatment, lesion scores were reduced from 45–83% and pruritus by 33–81%. Adverse effects included polyphagia, PU/PD, weight gain and/or intermittent GI signs. The benefit of long-term treatment with glucocorticoids must be weighed against the risk of adverse drug effects impacting on health and quality of life.
Cyclosporin at 5 mg/kg/day was found to be equally effective as prednisolone and methylprednisolone. After 6 weeks of treatment, the reduction of clinician-graded lesion scores was 52–67%. Similarly, decrease of owner-assessed pruritus was 36–100%. Vomiting and diarrhea were the most commonly seen adverse effects and seen in 14–42% but were mostly mild to moderate and a reason for cessation of therapy in less than 1% of the patients.3 Papillomatous eruptions and gingival hyperplasia were also seen occasionally.
Tacrolimus lotion as a topical calcineurin inhibitor was evaluated in several studies. At a concentration of 0.1%, it decreased clinician-assessed lesion scores and owner-assessed pruritus scores of localized atopic dermatitis by approximately 60% after 4–6 weeks of once- to twice-daily therapy. The only adverse effect seen in the studies using tacrolimus was mild and transient irritation at the site of application.
Oclacitinib is a selective Janus kinase 1 inhibitor recently introduced. In two large double-blinded, placebo-control trials, it provided rapid relief of canine pruritus associated with allergic disease and atopic dermatitis, respectively, at a dose of 0.4–0.6 mg/kg twice daily for 14 days, then once daily. Improvement in pruritus and lesion scores was 50–66% and 50%, respectively.4,5 Adverse effects were predominantly gastrointestinal disturbances and infections in a small number of dogs. The white blood cell count also decreased but stayed within the reference range in all dogs.
Histamine Receptor Antagonists
Most studies evaluating first-generation, sedating type 1 histamine receptor antagonists were neither blinded nor randomized or controlled. They provide conflicting evidence of efficacy for those antihistamines.1 However, adverse effects are rare and consist most commonly of drowsiness.1 One blinded RCT provided fair evidence of medium efficacy of a combination of hydroxyzine (25–100 mg/dog/day) and chlorpheniramine (1–4 mg/kg/day).6 An improvement of more than 50% in lesional scores was seen in 18% and of pruritus scores in 30% of the dogs, investigators judged the treatment satisfactory in 24% of the dogs. Another more recent double-blinded crossover study had similar results for this combination as well as for dimethindene maleate at a dose of 0.1 mg/kg/day.7
Of second-generation low-sedation type-1 histamine receptor antagonists, evidence for an effect on wheal formation after injection of histamine and anti-canine IgE was only demonstrated for cetirizine.8 As a group, there is conflictual evidence of benefit of type-1 histamine receptor antagonists for treatment of canine AD and based on current reports only hydroxyzine, cetirizine, dimethindene maleate and a combination of hydroxyzine and chlorpheniramine can be recommended based on current data.
Polyunsaturated Fatty Acids
There are a number of studies evaluating polyunsaturated fatty acids for the treatment of canine atopic dermatitis. In double-blinded, placebo-controlled studies, the difference between placebo and PUFA supplementation was typically significant; between 25 and 40% of patients responded favorably in the treatment groups.9 There is also evidence that concurrent administration of PUFAs decreases the requirements for glucocorticoids in atopic patients10 and that a combination of antihistamines and PUFAs is more effective than either therapy alone.11 Adverse effects of PUFA therapy were mild and typically consisted of diarrhea.
Papaverine, arofylline and pentoxifylline were all evaluated. Papaverine did not lead to satisfactory control of pruritus in an open, non-blinded, non-randomised trial, and arofylline showed a fair efficacy but unacceptable adverse effects. Pentoxifylline at 10 mg/kg twice daily for 4 weeks was found to be more effective than placebo; it reduced erythema scores by 30% and pruritus scores by 35%. Adverse effects were not noticed.
Leukotriene inhibitors have been evaluated for the treatment of canine atopic dermatitis in 4 trials, three of which were RCTs. Zafirlukast did show sustained fair to good reduction of pruritus in 2/18 dogs. With Zileuton treatment, erythema but not pruritus scores were significantly lower than those of placebo treatment. In two other trials with leukotriene antagonists, no difference in lesion and pruritus scores between the drug and placebo was found.1
A four-week open study and a three-week placebo-controlled blinded RCT evaluated the efficacy of treatment with the PGE1 analog misoprostol (5 µg/kg - 1 three times daily for up to six weeks). In both trials, lesional scores and pruritus were lower at the end of the study. At the end of the RCT, and compared to subjects receiving placebo, dogs treated with misoprostol exhibited significantly higher percentage reduction from baseline of pruritus scores, but not of lesional values. Adverse drug effects were mild and intermittent vomiting or diarrhea.
Although there are a number of studies evaluating the effect of ASIT on canine atopic dermatitis, most studies were retrospective and thus neither blinded nor controlled. Most of these studies report excellent efficacy in approximately 20% of the patients and good response in an additional 25–45%. The first prospective double-blinded, placebo-controlled study of ASIT in veterinary medicine reported 59% of 27 patients with significant improvement,12 but improvement was not evaluated with detailed clinical and pruritus scores used in more recent studies evaluating therapies for canine atopic dermatitis. Later, a double-blinded RCT comparing conventional with rush immunotherapy found significant improvement in pruritus, medication and clinical scores after 12 months of immunotherapy, there was no significant improvement with conventional immunotherapy.13
Topical Antipruritic Drugs
An open four-week trial evaluated two commercially available formulations of pramoxine-containing cream rinses. Overall, a good reduction (51–75%) in pruritus for 48 hours was assessed subjectively by the owners for seven dogs (41%).1 Another RCT compared the efficacy of whirlpool therapy with an antipruritic shampoo, conventional shampoo therapy and whirlpooling in water.14 Dogs improved significantly more with conventional shampooing and with shampoo therapy in the whirlpool compared to the control group, but there was no difference between the two modes of therapy. Similarly, shampooing dogs with allergies with an antipruritic shampoo or placebo showed significant improvement in both groups, but no difference between them.15 This topical shampoo therapy seems to improve pruritus, but evidence for significant influence of shampoo ingredients on such improvement is limited.
Although there is a need for randomized controlled trials to evaluate many drugs currently used or under investigation for the treatment of canine atopic dermatitis, published studies allow some conclusions. Currently, there is good evidence for a high efficacy of glucocorticoids such as prednisolone or methylprednisolone at a dose of 0.5–1 mg/kg q 24–48 hours, cyclosporine at a dose of 5 mg/kg q 24–48 hours and oclacitinib at 0.4–0.6 mg/kg twice daily for 14 days, then once daily and a medium efficacy of polyunsaturated fatty acids and topical tacrolimus at 0.1% daily. Fair evidence can be provided for medium efficacy of allergen-specific immunotherapy, pentoxifylline at 10–15 mg/kg q 12 hours, misoprostol at 5 mcg/ kg q 8 hours, dimethindene maleate at 0.1 mg/kg/day and a combination of chlorpheniramine and hydroxyzine at a dose of 1–4 and 25–100 mg/dog/day, respectively. For all other drugs evaluated, there was either not enough evidence provided, no sufficient treatment success was found, or adverse effects were too severe to recommend them routinely for the treatment of canine atopic dermatitis.
All this information is presented in more detail in a recent review published in Veterinary Dermatology.16 In addition, the International Task Force for Canine Atopic Dermatitis has developed practice guidelines for the treatment of canine atopic dermatitis that were published in Veterinary Dermatology17 and are available as PDF files for download at no cost in different languages on the Wiley-Blackwell website (http://onlinelibrary.wiley.com/doi/10.1111/j.1365-3164.2010.00889.x/suppinfo).
1. Olivry T, Mueller RS. Evidence-based veterinary dermatology: a systematic review on the pharmacotherapy of canine atopic dermatitis. Vet Dermatol. 2003;14:121.
2. Olivry T, Marsella R, Iwasaki T, Mueller RS. Validation of CADESI-03, a severity scale for clinical trials enrolling dogs with atopic dermatitis. Vet Dermatol. 2007;18:78.
3. Steffan J, Favrot C, Mueller RS. A systematic review and meta-analysis of the efficacy of cyclosporine for the treatment of canine atopic dermatitis. Vet Dermatol. 2006;17:3.
4. Cosgrove SB, Wren JA, Cleaver DM, et al. A blinded, randomized, placebo-controlled trial of the efficacy and safety of the Janus kinase inhibitor oclacitinib (Apoquel®) in client-owned dogs with atopic dermatitis. Vet Dermatol. 2013;24:587.
5. Cosgrove SB, Wren JA, Cleaver DM, et al. Efficacy and safety of oclacitinib for the control of pruritus and associated skin lesions in dogs with canine allergic dermatitis. Vet Dermatol. 2013;24:479.
6. Ewert G, Daems T. Treatment of canine atopic dermatitis by a fatty acid copolymer: comparative double blind study. Prat Med Chir Anim Comp. 2001;36:401.
7. Eichenseer M, Johansen C, Mueller RS. Efficacy of dimetindene and hydroxyzine/chlorpheniramine in atopic dogs: a randomised, controlled, double-blinded trial. Vet Rec. 2013;173:423.
8. Bizikova P, Papich MG, Olivry T. Hydroxyzine and cetirizine pharmacokinetics and pharmacodynamics after oral and intravenous administration of hydroxyzine to healthy dogs. Vet Dermatol. 2008;19:348.
9. Mueller RS, Fieseler KV, Fettman M, et al. Effect of omega-3 fatty acids on canine atopic dermatitis. J Small Anim Pract. 2004;45:293.
10. Bond R, Lloyd DH. Combined treatment with concentrated essential fatty acids and prednisone in the management of canine atopy. Vet Rec. 1994;134:30.
11. Paterson S. Additive benefits of EFAs in dogs with atopic dermatitis after partial response to antihistamine therapy. J Small Anim Pract. 1995;36:389.
12. Willemse A, et al. Effect of hyposensitization on atopic dermatitis in dogs. J Am Vet Med Assoc. 1984;184:277.
13. Mueller RS, Fieseler KV, Zabel S, Rosychuk RAW. Conventional and rush immunotherapy in canine atopic dermatitis. In: Hillier A, Foster AP, Kwochka KW, eds. Advances in Veterinary Dermatology V. Oxford, Seiten: Blackwell Publishing; 2005:60–69.
14. Loeflath A, von Voigts-Rhetz A, Jaeger K, Mueller RS. The efficacy of a commercial shampoo and whirlpooling in the treatment of canine pruritus - a double-blinded, randomized, placebo-controlled study. Vet Dermatol. 2007;18:427.
15. Schilling J, Mueller RS. Double-blinded, placebo-controlled study to evaluate an antipruritic shampoo for dogs with allergic pruritus. Vet Rec. 2012;171:97.
16. Olivry T, Foster AP, Mueller RS, McEwan NA, Chesney C, Williams HC. Interventions for atopic dermatitis in dogs: a systematic review of randomized controlled trials. Vet Dermatol. 2010;21:4.
17. Olivry T, DeBoer DJ, Favrot C, Jackson HA, Mueller RS, Nuttall T, Prélaud P. Treatment of canine atopic dermatitis: 2010 clinical practice guidelines from the International Task Force on Canine Atopic Dermatitis. Vet Dermatol. 2010;21:233.