What's new in dermatologic therapy?

Dermatologic problems can be frustrating to treat. Pentoxifylline, tacrolimus, pimecrolimus, interferon, and imiquimod offer potential new therapeutic options. Although few veterinary studies showing positive results with these drugs are available, veterinary dermatologists have been using them with varying degrees of success. This article highlights what has worked for us and other veterinary dermatologists and discusses the results of drug studies.

PENTOXIFYLLINE

Pentoxifylline is a member of a class of drugs that inhibit phosphodiesterase (PDE) enzymes, referred to as PDE inhibitors. Pentoxifylline makes red blood cells more pliable and decreases blood viscosity. It also decreases fibronectin, reduces the production of cytokines (tumor necrosis factor-alpha, interleukin-1, interleukin-6, interleukin-8), decreases leukocyte response to interleukin-1, impairs t lymphocyte binding to keratinocytes, decreases fibroblast activity, and, with long-term use, may decrease fibrosis.1,2

Figure 1. A dog with dermatomyositis. Note the alopecia, hyperpigmentation, and scarring on the front limbs, muzzle, and periocular region.

Pentoxifylline is beneficial in treating a variety of canine skin diseases.3-5 Its effectiveness may be due to any one or a combination of its different actions on the immune response. Pentoxifylline has been evaluated most thoroughly in well-designed studies for treating atopic dermatitis3 and has been reported effective in treating dermatomyositis4 (Figures 1 & 2) and contact dermatitis.5

Figure 2. The same dog as in Figure 2 four months after beginning pentoxifylline therapy. Note the resolution of the lesions.

Veterinary dermatologists have also recommended pentoxifylline to treat vasculitis, ischemic dermatopathy, pinnal thrombovascular necrosis, idiopathic mucinosis, and erythema multiforme and as an adjunctive therapy for idiopathic onychomadesis, immune-mediated dermatoses, fibrosing deep pyoderma, and pododermatitis. However, studies supporting pentoxifylline's efficacy in treating these conditions are lacking. For example, only one of seven dogs with cutaneous vasculitis exhibited a definitively favorable response to pentoxifylline treatment,6 and only two of five dogs with lupoid onychodystrophy showed excellent treatment responses.7 Poor responses were seen in four of four dogs with vesicular cutaneous lupus erythematosus treated with pentoxifylline alone or in combination with other drugs.8

Initially, many veterinary dermatologists administered 10 mg/kg pentoxifylline orally two or three times a day. It has been suggested that a frequency of three times a day might be preferable for some diseases, such as atopic dermatitis.9 In addition, some veterinary dermatologists have reported doses of 15 to 25 mg/kg to be more effective than 10-mg/kg doses. One study showed a good response in 10 of 10 dogs with dermatomyositis at an average dosage of 25 mg/kg (range 18 to 31 mg/kg) given orally twice a day. The median response time was six weeks with a range of four to 10 weeks.4

A pharmacokinetic study in dogs showed that after a single oral dose of 30 mg/kg pentoxifylline, plasma pentoxifylline concentrations reached 1,000 ng/ml (the therapeutic concentration in people) and persisted for 510 minutes (± 85 min), suggesting that twice-a-day administration may be effective at that dose.10 However, one caution is that bioavailability varied from about 25% to 75%.10 In contrast, another study in dogs showed that 15 mg/kg given orally three times a day produced plasma concentrations equivalent to therapeutic concentrations in people.11

The efficacy of generic pentoxifylline is uncertain. No comparative studies exist, but some veterinary dermatologists report better responses to the brand name formulation Trental (Sanofi-Aventis).

No serious adverse effects of pentoxifylline have been reported with any frequency in dogs. Vomiting and diarrhea are the major concerns in dogs and are dose-related in people. Two dogs receiving pentoxifylline reportedly developed erythema multiforme12 ; however, one author (Griffin) has used it to treat erythema multiforme with some cases showing a beneficial effect.

No studies have evaluated the use of pentoxifylline in cats. However, veterinary dermatologists have used it for atopic dermatitis, ischemic dermatopathy, and nonhealing deep bacterial infections in cats at doses of 100 mg given orally twice a day or 10 mg/kg given orally twice a day with variable success and no observed adverse effects.

TACROLIMUS

Tacrolimus, a macrolide produced by Streptomyces tsukubaensis, is available in oral and injectable formulations (Prograf—Astellas Pharma) and has been used extensively as an immunosuppressive in human transplant patients. Side effects from the systemic use of tacrolimus (Prograf) in dogs are severe and preclude systemic use of this drug in dogs; these side effects include weight loss, vomiting, and diarrhea.13 Protopic (Astellas Pharma), a topical formulation available as a 0.1% ointment, was the first Food and Drug Administration (FDA)-approved topical immunomodulator. These drugs have topical anti-inflammatory effects without the cutaneous atrophy-inducing and metabolic effects of topical glucocorticoids.

Tacrolimus was recently approved for treating atopic dermatitis in people and is also beneficial in treating psoriasis and possibly alopecia areata. Large multicenter clinical studies in people indicate that it is a safe drug with minimal systemic absorption. Its mechanism of action is similar to cyclosporine's, but tacrolimus is 10 to 100 times more potent. It works by calcineurin inhibition, resulting in suppression of antigen-presenting T cells, inhibition of the production of multiple cytokines from T cells (interleukin-2, interleukin-3, interleukin-4, interferon, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor), down regulation of cytokine expression in other cells (mast cells, basophils, eosinophils, keratinocytes, and Langerhans cells), and inhibition of eosinophil recruitment.14

Topical tacrolimus has been reported to be effective in treating canine perianal fistulas (Figure 3), although it is less effective than systemic cyclosporine.15 It is used to maintain control of perianal fistulas once a sufficient response to cyclosporine occurs. It also reduces the severity of localized skin lesions of canine atopic dermatitis16,17 and may be useful in treating localized lesions associated with discoid lupus erythematosus and pemphigus foliaceus.18 Veterinary dermatologists have used it for a variety of veterinary dermatologic diseases in which lesions are localized, and one author (Griffin) has used the topical formulation to treat alopecia areata and vitiligo.

Figure 3. A perianal fistula in a dog.

For both tacrolimus and pimecrolimus (discussed below), the FDA has issued a public health advisory warning of a potential cancer risk based on information from animal studies and case reports in a small number of patients. In the authors' practice, clients are advised of this warning and are advised to wear gloves when applying these drugs. No studies evaluating this potential cancer risk in dogs and cats have been conducted.

PIMECROLIMUS

Pimecrolimus (Elidel—Novartis) is an ascomycin macrolactam derivative that acts similarly to tacrolimus, although a recent study showed that it exerts a more selective immunomodulatory effect.19 In mice, pimecrolimus effectively inhibited the secondary elicitation phase that is the clinical manifestation of contact hypersensitivity, but it did not impair the primary immune response, or sensitization phase, in contrast to tacrolimus and cyclosporine.19 No studies comparing pimecrolimus and tacrolimus use in dogs have been done, but veterinary dermatologists report that the efficacy of pimecrolimus is similar to or less than that of tacrolimus.

Table 1 Five Selected New Drugs Used in Veterinary Dermatology

INTERFERON

Interferons are a group of glycoprotein cytokines produced by a variety of inflammatory cells and fibroblasts that have numerous immunologic effects, including antiviral, antiproliferative, and immunomodulatory activities. Several recognized interferons exist, and they vary in their immunologic effects. Their main uses are based on interferon's antiviral and antineoplastic properties, but they may also be beneficial in treating a variety of dermatologic disorders.

The initial commercial form is the recombinant human interferon alfa-2a (Roferon-A—Hoffman-La Roche). The high potency Roferon-A comes as a 3 million-IU solution in a 1-ml vial. The vial contents are then diluted into 999-ml sterile saline and then divided into 10-ml ampules (3,000 IU/ml) that will remain stable if frozen, according to other veterinary dermatologists. (It has also been described as being further diluted to 1,000 IU/ml.) Once thawed, an ampule should be refrigerated and will remain effective for 30 days. The refrigerated 3,000-IU/ml ampule is used in 0.33-ml (1,000 IU) increments given orally daily. This low-dose oral therapy makes the treatment reasonably priced, as the 3 million-IU vial costs about $40. Instead of the dosage above, some veterinary dermatologists administer 3,000 IU/ml once every three days. The solution is injected into the oral cavity since oromucosal administration induces beneficial systemic effects in animals and people.20 This regimen has been used for canine papillomavirus.21 No studies comparing these different protocols exist, and limited information describing Roferon-A's effectiveness in dogs and cats is available.

Human recombinant interferon alpha-2b was evaluated in a pilot study for idiopathic recurrent pyoderma in dogs, and the results suggested only transient benefit at oral dosages of 1,000 IU/ml/day.22 Veterinary dermatologists have also seen feline herpesvirus infection, idiopathic facial dermatitis, and eosinophilic ulcers respond to low-dose oral therapy regimens of interferon alpha-2b.

The use of recombinant feline interferon-omega (Virbagen Omega—Virbac) has been studied for the treatment of several nondermatologic conditions. When administered intravenously at high doses, it improved the clinical signs and reduced the mortality of canine parvoviral infection.23,24 When administered subcutaneously at high doses, it markedly improved the clinical signs and survival rates of cats infected with feline leukemia virus.25 In addition, it was successfully used to treat chronic gingivostomatitis in a cat when given subcutaneously then orally.26

Recently, a pilot study suggested that Virbagen Omega was effective in treating atopic dermatitis in dogs,27 and a case of feline herpesvirus-induced facial dermatitis was successfully treated with high-dose subcutaneous and intralesional injections of feline interferon-omega.28 All other veterinary dermatologic uses are based on anecdotal information and include the treatment of canine oral papillomavirus infections, recurrent pyoderma, and mycoses fungoides.

A recombinant canine interferon-gamma cloned in Japan was shown in a clinical trial to be significantly more effective in treating canine atopic dermatitis than topical diphenhydramine was.29

IMIQUIMOD

We are excited about imiquimod (Aldara—3M Pharmaceuticals) because it is topically applied, has few side effects in people, and appears to stimulate natural immune function, particularly antiviral and antitumor responses. It has been shown to activate intracellular signaling pathways through Toll-like receptor (TLR) 7 and TLR8, resulting in the production of proinflammatory cytokines, in addition to having other undetermined mechanisms of action.30 It is being prescribed for a wide variety of diseases in people including keloids,31 virus-induced warts,32,33 molluscum contagiosum (a human poxvirus infection),34 and epithelial premalignant or neoplastic diseases such as squamous cell carcinoma in situ,35 extramammary Paget's disease,36 actinic keratosis,37 and basal cell carcinoma.38 This drug will undoubtedly find more uses in veterinary medicine; imiquimod may be a valuable therapy for a variety of cutaneous viral lesions and epithelial diseases in cats, particularly actinic keratosis, squamous cell carcinoma, and Bowen's disease. For most conditions in people, it is applied two or three times weekly for various intervals. Burning or irritant reactions are the major side effects. No studies have evaluated the use of this drug in dogs and cats, but one pilot study had positive results treating equine sarcoids with imiquimod.39

In our practice, imiquimod has been used successfully to treat two forms of canine papillomavirus infection (Figure 4), feline herpesvirus infection, feline papillomas, feline Bowen's disease, and equine sarcoids. No side effects have been seen so far. The drug may be helpful for solar dermatitis and precancerous solar-induced lesions in dogs and cats if the lesions are localized. Irritancy seems to be an individual response, with horses and cats seemingly more sensitive than dogs. We are applying it topically from two to four consecutive days a week at a dose of one packet (0.25 g) given over two or three days. Generally we only treat some of the lesions and have seen untreated lesions also respond. It is available in boxes containing 12 doses for about $140, and a single dose can be dispensed to use for multiple applications.

Figure 4. Papillomavirus infection near a footpad in a dog (before therapy) that responded to imiquimod.

Heide M. Newton, DVM, DACVD

Craig E. Griffin, DVM, DACVD

Animal Dermatology Clinic

5610 Kearny Mesa Road

San Diego, CA 92111

REFERENCES

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19. Meingassner JG, Fahrngruber H, Bavandi A. Pimecrolimus inhibits the elicitation phase but does not suppress the sensitization phase in murine contact hypersensitivity, in contrast to tacrolimus and cyclosporine A. J Invest Dermatol 2003;121(1):77-80.

20. Cummins JM, Krakowka GS, Thompson CG. Systemic effects of interferons after oral administration in animals and humans. Am J Vet Res 2005;66(1):164-176.

21. Stokking LB, Ehrhart EJ, Lichtensteiger CA, et al. Pigmented epidermal plaques in three dogs. J Am Anim Hosp Assoc 2004;40(5):411-417.

22. Thompson LA, Grieshaber TL, Glickman L, et al. Human recombinant interferonalpha-2b for management of idiopathic recurrent superficial pyoderma in dogs: a pilot study. Vet Ther 2004;5(1):75-81.

23. Martin V, Najbar W, Gueguen S, et al. Treatment of canine parvoviral enteritis with interferon-omega in a placebo-controlled challenge trial. Vet Microbiol 2002;89(2-3):115-127.

24. de Mari K, Maynard L, Eun HM, et al. Treatment of canine parvoviral enteritis with interferon-omega in a placebo-controlled field trial. Vet Rec 2003;152(4):105-108.

25. de Mari K, Maynard L, Sanquer A, et al. Therapeutic effects of recombinant feline interferon-omega on feline leukemia virus (FeLV)-infected and FeLV/feline immunodeficiency virus (FIV)-coinfected symptomatic cats. J Vet Intern Med 2004;18(4):477-482.

26. Southerden P, Gorrel C. Treatment of a case of refractory feline chronic gingivostomatitis with feline recombinant interferon omega. J Small Anim Pract 2007;48(2):104-106.

27. Carlotti D, Madiot G, et al. Use of recombinant omega interferon therapy in canine atopic dermatitis: a pilot study. Vet Dermatol 2004;15(s):32.

28. Gutzwiller ME, Brachelente C, Taglinger K, et al. Feline herpes dermatitis treated with interferon omega. Vet Dermatol 2007;18(1):50-54.

29. Iwasaki T, Hasegawa A. A randomized comparative clinical trial of recombinant canine interferon-gamma (KT-100) in atopic dogs using antihistamine as control. Vet Dermatol 2006;17(3):195-200.

30. Schon MP, Schon M, Klotz KN. The small antitumoral immune response modifier imiquimod interacts with adenosine receptor signaling in a TLR7- and TLR8-independent fashion. J Invest Dermatol 2006;126(6):1338-1347.

31. Berman B, Kaufman J. Pilot study of the effect of postoperative imiquimod 5% cream on the recurrence rate of excised keloids. J Am Acad Dermatol 2002;47:S209-211.

32. Carrasco D, vander Straten M, Tyring SK. Treatment of anogenital warts with imiquimod 5% cream followed by surgical excision of residual lesions. J Am Acad Dermatol 2002;47(4 Suppl):S212-216.

33. Housman TS, Jorizzo JL. Anecdotal reports of 3 cases illustrating a spectrum of resistant common warts treated with cryotherapy followed by topical imiquimod and salicylic acid. J Am Acad Dermatol 2002;47(4 Suppl):S217-220.

34. Skinner RB Jr. Treatment of molluscum contagiosum with imiquimod 5% cream. J Am Acad Dermatol 2002;47(4 Suppl):S221-224.

35. Orengo I, Rosen T, Guill CK. Treatment of squamous cell carcinoma in situ of the penis with 5% imiquimod cream: a case report. J Am Acad Dermatol 2002;47(4 Suppl):S225-228.

36. Zampogna JC, Flowers FP, Roth WI. Treatment of primary limited cutaneous extramammary Paget's disease with topical imiquimod monotherapy: two case reports. J Am Acad Dermatol 2002;47(4 Suppl):S229-235.

37. Persaud A, Lebwohl M. Imiquimod cream in the treatment of actinic keratoses. J Am Acad Dermatol 2002;47(4 Suppl):S236-239.

38. Cowen E, Mercurio MG, Gaspari AA. An open case series of patients with basal cell carcinoma treated with topical 5% imiquimod cream. J Am Acad Dermatol 2002;47(4 Suppl):S240-248.

39. Nogueira SA, Torres SM, Malone ED, et al. Efficacy of imiquimod 5% cream in the treatment of equine sarcoids: a pilot study. Vet Dermatol 2006;17(4):259-265.