Canine atopic dermatitis is a chronic often frustrating disease to treat. In the last few years there have been several new therapies that have been shown to be helpful or possible valuable in managing atopic dermatitis.
Cyclosporine (Atopica®) was initially shown to be effective for treating atopic dermatitis in 2002. (Olivry, Rivierre et al. 2002; Olivry, Steffan et al. 2002) Those along with many other studies have extensively evaluated the drug. It is the first alternative therapy to glucocorticoids that has shown similar efficacy to prednisolone and methylprednisolone. Cyclosporin has multiple effects on the skin immune and inflammatory response. Originally the mode of action was felt to be relatively specific for effects on T helper lymphocytes. Cyclosporin complexes bind calcineurin and inhibit the signal transduction to the nucleus resulting in blocked or impaired synthesis of multiple cytokines, most notably interleukin-2 (IL-2) and inhibits T-cell proliferation and the formation of cytotoxic lymphocytes. Cyclosporine is also thought to inhibit, via suppression of calcium-mediated signal transduction, mast cells and IgE-mediated immediate and LPR reactions. A recent study in dogs showed that suppression of mRNA for IL-2, IL-4 and gamma interferon but not TNF alpha as described in humans.(Kobayashi, Momoi et al. 2006) In additions dogs do not have an up regulation of TGF beta as in man. These results suggest species differences may occur. Multiple studies have demonstrated influences on mast cells, Langerhans cells, keratinocytes, eosinophils and lymphocytes. Cyclosporine has immunosuppressive and antiproliferative affects rather than cytotoxic or myelotoxic effects. It is likely that the numerous disease and types of disease that may respond to cyclosporine attest to the multitude of effects the drug may have.
The dose is 5mg/kg q24h. Once a response is seen then the dose may be tapered. In some cases it is better to continue the induction dose until clinical improvement is complete or reached a steady state of response. Tapering is done by maintaining the dose at 5mg/kg but changing to q48h and with continued response is further tapered to q72 or every q 4-7d dosing. In some cases long term remissions may be seen once the drug is discontinued, though the frequency of this needs to be determined in more controlled study. It make take several months for signs to return and this effect is another way to manage some cases, by going on and off the drug long term. This is another way to keep the costs of therapy within a clients comfort level. Some dogs may end up on relatively low levels of drug long term by doing the tapering or going on an off the drug. This makes the overall cost low enough to have even large dogs that initially may seem to expensive to treat actually respond well at an affordable cost.
Adverse reactions have been reported in a study of up to 268 atopic dogs (Steffan, Parks et al. 2005). The most commonly encountered side effects are vomiting and diarrhea. Vomiting is often short term or administration with food may alleviate it. In other cases temporary concurrent use of metoclopromide 0.2 to 1mg/kg q24h may allow continued use. For diarrhea temporarily stopping the drug then treating again with the addition of metronidazole or fiber to the diet may alleviate the diarrhea. However this has been the most common medical reason the drug has to be discontinued. Hirsutism and gingival hyperplasia have also been seen at the doses used for atopic disease. Hirsutism is often a generalized thickened more dense hair coat often associated with increased shedding. In other cases there are patterns where the hair growth is exceptionally long. This seems to most often affect the paws and head or face region. Papillomatous hyperplasia may also be seen and infrequently is viral and more often bacterial. Bacterial infections may appear as atypical lesions. Nephrotoxicity and hepatic toxicity has not been observed in dogs, as a significant problem. This is more of a concern when ketoconazole is used for concurrently either for Malassezia or as dose sparing agent. Elevated blood pressure is concern in humans and though rare in dogs should be monitored for. In humans there is an increased risk for malignancy especially skin neoplasia with cyclosporine use.
Topical Immunomodulators (TIMs) are a new class of drugs that have been approved in humans for the treatment of atopic dermatitis. The initial approved formulation, Tacrolimus, has also been shown effective in dogs with atopic dermatitis, especially localized disease.(Marsella, Nicklin et al. 2004; Bensignor and Olivry 2005) Tacrolimus is a 23-member macrolide produced by Streptomyces tsukabaensis and the topical formulation is called Protopic® an ointment available as a 0.1% or 0.03%. The other approved drug in this category is Pimecrolimus (Elidel®) which is an ascomycin macrolactam derivative that acts similar to Tacrolimus. It is used similar to Protopic though studies documenting it efficacy have not been done. No comparisons have been done in dogs but anecdotal reports suggest that in some dogs it is less irritating and the cream base is preferred by some clients.
The TIMs have topical anti-inflammatory effects without the atrophogenic effects and metabolic effects of topical glucocorticoids. The mechanism of action is similar to cyclosporine by inhibition of calcineurin, but 10 to 100 times more potent. Large multicenter human studies indicate it is a very safe drug with minimal systemic absorption. However animal studies have shown an increase risk for skin cancers and there is a concern that humans with long term use may also be predisposed to skin cancers including melanoma and possible lymphoma. This led the Food and Drug Administration to include this warning on the label and now recommend these drugs in more limited settings when other forms of therapy have been ineffective.
These drugs are used for localized atopic dermatitis that is not effective to topical glucocorticoids. Initial treatment is a light application of the ointment or cream until it is completely rubbed in twice daily for two weeks. If a response is seen the frequency may be lowered to once daily or less. To date problems other than irritancy have not been noted in dogs.
Interferons (INF) are a group of glycoprotein cytokines produced by a variety of inflammatory cells and fibroblasts that have numerous immunologic effects. There are several recognized interferons and they do vary in their immunologic effects. The initial commercial form of interferon is the recombinant human INF alpha-2b (Roferon-A®) and more recently a veterinary product became available. Carlotti used recombinant feline INF-omega (Virbagen®, Omega) has been shown helpful in an open trial of atopic dogs. A small open pilot trial with canine interferon gamma also suggests efficacy at high doses.(Iwasaki, Park et al. 2005) Interferon alpha (Roferon®) comes as a 3 million IU/ml solution and is diluted in 999ml lactated ringers and then divided into 30 ml ampoules that anecdotally will remain stable if frozen. Once thawed it is kept refrigerated for thirty days. The refrigerated ampoule is then used at 0.33 ml, 1,000IU given orally daily. The oral administration is done by injecting the solution in the buccal cavity as it is believed the absorption is from the upper oral mucosa. Anecdotally they are cases convinced that this low dose regimen if effective and also have used it concurrently with allergen specific immunotherapy. Controlled studies are needed to see if it improves the efficacy of ASIT.
Nutraceuticals and herbal remedies are also being evaluated in management of chronic pruritus and atopic disease. Controlled studies and studies on mechanism are needed. It has been suggested that some ingredients may be helpful but since many new diets have higher levels of omega 3 fatty acids this may also improve these patients.
References
1. Bensignor, E. and T. Olivry (2005). "Treatment of localized lesions of canine atopic dermatitis with tacrolimus ointment: a blinded randomized controlled trial." Vet Dermatol 16(1): 52-60.
2. Iwasaki, T., S. Park, et al. (2005). Effect of treatment with recombinant canine IFN-g on the clinical signs, histopathology and Th1/Th2-cytokine mRNA profiles in Shih Tzu dogs and a Basset hound with atopic dermatitis. Advances in Veterinary Dermatology. A. Hillier, A. Foster and K. Kwochka. Oxford, Blackwell Publishing. 5: 82-88.
3. Kobayashi, T., Y. Momoi, et al. (2006). Cyclosporine inhibits IL-2, IL-4 and IFN-gamma mRNA expression, but not TNF-alpha in canine peripheral blood mononuclear cells. Nt Am Vet Derm Forum, Palm Springs.
4. Marsella, R., C. F. Nicklin, et al. (2004). "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." Vet Dermatol 15(5): 294-303.
5. Olivry, T., C. Rivierre, et al. (2002). "Cyclosporine decreases skin lesions and pruritus in dogs with atopic dermatitis: a blinded randomized prednisolone-controlled trial." Veterinary Dermatology 13(2): 77-87.
6. Olivry, T., J. Steffan, et al. (2002). "Randomized controlled trial of the efficacy of cyclosporine in the treatment of atopic dermatitis in dogs." J Am Vet Med Assoc 221(No 3): 370-377.
7. Steffan, J., C. Parks, et al. (2005). "Clinical trial evaluating the efficacy and safety of cyclosporine in dogs with atopic dermatitis." J Am Vet Med Assoc 226(11): 1855-1863.