Topical and systemic therapy for seborrheic disorders: Parts 1 and 2 (Proceedings)

The use of topical therapeutics and in particular shampoo therapy, has gained increasing popularity in veterinary dermatology. Shampoos are one of the easiest and most complete vehicles to utilize when applying topical therapeutics. It can be extremely beneficial in the management of seborrheic disorders. In many cases it can be used as a sole therapy or as an adjunctive therapy often minimizing the need for systemic therapy. Owner compliance can sometimes be a problem with this type of therapy, since it may be difficult and time consuming for owners to do. However it does allow many owners to actively participate in the management of their pets' skin condition.

Gaining familiarity with the products that are commercial available is very important. Many products are not closely regulated regarding their active ingredients or formulations, so first hand experience is very important. . By utilizing the shampoos on your own pets and patients you can gain experience regarding the potency, stability, efficacy and safety of a product and feel knowledgeable about recommending these products to clients for their pet's skin conditions

Systemic options include fatty acid supplements, zinc supplementation, vitamin A, retinoids, and calcitriol. Of these systemic choices fatty acid supplements are the most commonly routinely utilized. Vitamin A is also relatively commonly used and has minimal toxicity. Retinoids and calcitriol are rarely used due to expense and greater chance for toxic reactions.

Table I – Antiseborrheic Shampoos

Topical Therapy

Antiseborrheic shampoos function by normalizing keratinocyte turnover. A keratoplastic effect is optimal for an antiseborrheic shampoo to be effective. This is where the rate of division of the basal cells is reduced. Most antiseborrheic shampoos also have a keratolytic effect, where there is an elimination of excess corneal layers, by increasing desquamation. This is thought to be due to a softening and a reduction of the intercellular connection of the corneocytes resulting in increased desquamation of the stratum corneum. There are many keratoplastic and keratolytic agents that are commercially available in shampoo formulations (Table I). Also many moisturizing shampoos that are used for allergic skin disease management can also be used in mild dryer forms of keratinization defects. These function primarily by increasing the moisture content of the skin, with many products also having emollient effects (Table II)

Table II – Moisturizing Products

Salicylic Acid and Sulfur Shampoos

Salicylic acid is a keratolytic agent. It causes a reduction in skin pH, which leads to an increase in the amount of water that the keratin of the stratum corneum is able to absorb. In the desquamation process it has a direct effect on intercellular cement and intercellular junction system (desmosomes). These actions help soften the corneal layer. Salicylic acid acts synergistically with sulfur, and is often present in equal quantities in shampoos. Its efficacy varies with concentration. Sulfur is mildly keratolytic. It forms hydrogen sulfide in the corneal layer and has numerous other antiseborrheic properties. It is also keratoplastic, due to a direct cytostatic effect and possibly because it interacts with epidermal cysteine to form cystine, an important component of the corneal layer. It is also antiseptic. Sulfur can be very drying and can also have an odor depending on its formulation. It exerts synergistic activity with salicylic acid most effectively when both substances are incorporated into the shampoo in equal concentrations. The author's favorite combination salicylic acid and sulfur products are: Sebolux ®,Virbac, Sebalyt ® and SeboRx ® – IVAX/DVM Pharmaceuticals and SebaMoist ® and SebaHex ®Vetoquinol, and DermaSebS Shampoo ®,Dermapet. Sulfur and salicylic acid shampoos work best for light scaling and flaking keratinization defects.

Tar Shampoos

Tar is a keratoplastic agent. It reduces nuclear synthesis in the epidermal basal layers. It is also antiseptic and antipruritic. There are many different sources and varieties of this active agent. Skin drying, discoloration of light colored coats and irritation can be seen with tar-based products but are more common when the concentration is above 3%. There is also some concern about coal tar based products being carcinogenic and some products containing coal tar will have labeling warning of this concern. Tar shampoos are contraindicated in the cat due to a much higher degree of irritancy and in some cases making cats systemically ill. . Because of the increased effectiveness of other non-tar products the author rarely uses tar-based products. If necessary in more severe forms of seborrhea, particularly in some variants of idiopathic cocker seborrhea or severe forms of sebaceous adenitis, the author will use: Solubilzed tar: T-lux ®, Virbac, 2% tar and salicylic acid: NuSalT ® – IVAX/DVM Pharmaceuticals or even more potent tars: Vetoquinol Tar ®, Lytar ®, DVM Pharmaceuticals and Allerseb T ®, Virbac. Because of their potency and potential side effects it is critical to make sure all tar shampoos are completely rinsed off.

Selenium Disulfide Shampoos

Selenium disulfide is keratolytic and keratoplastic by reducing epidermal turnover and impairing disulfide bridge formation in keratin. It is also antiseborrheic but has strong detergent, irritant and drying effects. It is also contraindicated in the cat for the same reasons listed for tars. The author rarely uses this shampoo but on occasion can be of value in very greasy, oily keratinization defects with concurrent yeast dermatitis where client finances are a concern as it is less expensive and available over the counter.

Benzoyl Peroxide Shampoos

Benzoyl peroxide is often thought of as being antibacterial but it is also antiseborrheic, by hydrolyzing sebum and reducing sebaceous gland activity. Benzoyl peroxide exerts a follicular flushing action, which is very useful when treating comedone disorders and/or follicular hyperkeratosis. Irritant side effects have been reported especially in concentrations above 5%. The skin may also become dry and emollients can be applied after using this product. Many of the newer benzoyl peroxide products have moisturizing agents added to prevent excessive drying. The author's favorite benzoyl peroxide product to use in seborrheic conditions is Sulfoxydex ®,IVAX/DVM Pharmaceuticals because of the synergistic effects that the sulfur adds to the benzoyl peroxide. The most common products used are listed in the antibacterial shampoo section.

Zinc gluconate and pyridoxine shampoos

Zinc gluconate has antiseborrheic properties. Zinc, is a type 1 5-reductase inhibitor, down regulates sebum production, and is used in human dermatology to treat acne vulgaris, both topically and orally. Vitamin B6 (pyridoxine) also plays a role in sebum secretion and there is a synergistic effect of unknown mechanism with zinc. Zinc gluconate and vitamin B6 are combined with essential fatty acids in a newer shampoo that has both antiseborrheic and antibacterial properties (Keratolux ®, Virbac) .

Phytosphingosine Shampoos, Sprays and Spot-on Products

Phytosphingosine (PS) based topical therapies have been recently introduced into the US in the last 2 years (Douxo®, Sogeval) that utilizes a unique ingredient called phytosphingosine (PS). PS is a key molecule in the natural defense mechanism of the skin. It is a component of ceramides, 40 –50% of the main lipids responsible for maintaining the cohesion of the stratum corneum, controlling local flora and maintaining the correct moisture balance. Specific seborrheic cases can be treated with a variety of phytosphingosine formulations. Douxo®, Seborrhea Shampoo is at the center of the phytosphingosine protocols that requires fewer treatments than standard shampoo-only anti-seborrhea protocols. It is designed to work in combination with Douxo®, Seborrhea Micro-emulsion Spray and Spot-on, all containing phytosphingosine. Moisturizing Douxo®, Seborrhea Micro-emulsion Spray can be combined with Douxo®, Seborrhea Shampoo in a protocol that provides efficacy with the convenience of a few pumps that spray a fine mist rather than completely bathing. This is an option to standard shampoo only, seborrhea treatment and can reduce the frequency and time commitment of just shampoo therapy alone. For treatment of localized seborrheic lesions, otitis externa, or when shampooing is not an option, Douxo®, Seborrhea Spot-on with 1% phytosphingosine provides efficacy. It is particularly valuable for localized and specific keratinization defects (see section on localized keratinization defects). Phytosphingosine helps control the seborrheic disorders associated with pyoderma. For cases complicated by secondary bacterial or yeast infections a specific formulation Douxo®, Chlorhexidine PS with 3% chlorhexidine and phytosphingosine can be utilized. Phytosphingosine also has anti-inflammatory properties and has value for allergic skin disease management and a specific allergy control formulation is available Douxo® Calm.

Cyclosporine

Cyclosporine has recently been evaluated for use in certain keratinization defects, most notably sebaceous adenitis. In one report, 20 cases of sebaceous adenitis were treated with a cyclosporine (Neoral ® Novartis) oral solution; 250 ml of a100mg/ml solution was applied to the coat daily followed by emollient sprays. After 6 weeks of therapy all cases showed response and many cases were able to reduce applications to 1-2 x a week. No detectable systemic cyclosporine levels were found on serum measurements. The author has also used tacrolimus (Protopic ®, Fujisawa) with occasional success in localized forms of sebaceous adenitis in the Standard poodle. Its use and application concerns are previously discussed in the topical therapy for allergic skin disease section.

Emollients and Moisturizing Agents

These products are often used after antiseborrheic shampoos especially in dryer forms of seborrhea. There are a variety of products available in crème rinse, spray rinses and leave-on spray formulations. The author's favorites are Hy-Lyt efa ®, and Relief ® IVAX/DVM Pharmaceuticals, Humilac ® and Epi-Soothe ® Virbac and Dermal Soothe Hydra-Pearls cream rinse ®, Vetoquinol. Many of these products have essential fatty acids, moisturizing and emollient agents to replace loss of essential fatty acids and to restore proper hydration to the epidermis. Some products can actually be used in place of the shampoo that contain not only moisturizing agents but active anti-inflammatory, antiseborrheic and antimicrobial agents and applied in between bathing, ie Duoxo Calm ®, Sogeval.

Systemic Therapy Options

Essential Fatty Acids

Essential fatty acids may be helpful in the management of all scaling disorders. It is particularly beneficial in cases where the coat and skin are characterized by excessive dry scaling and flaking. However, they may also be beneficial in cases where moderate greasy and oily conditions present. By over supplementing with the correct essential fatty acids some of these greasier and oily cases may show clinical improvements. The author prefers the use of balanced omega 3 and 6 fatty acids when utilizing these products for these conditions. If pruritus is a major factor than straight omega 3 fatty acids can be selected. On occasion fatty acids can create diarrhea, pancreatitis and platelet clotting abnormalities. A variety of products are available by many of the top dermatological therapeutic companies. The author will commonly use Derm caps and 3 – V caps ® IVAX/DVM Pharmaceuticals and EFA caps ® Virbac.

Zinc

Special syndromes have been recognized that have been described as "zinc responsive dermatitis" These can be due to a genetic tendency towards poor zinc absorption or metabolism as seen in the Siberian Husky breed, a true dietary zinc deficiency or foods that are high in calcium or plant phytate that bind zinc and cause a relative zinc reduction in the diet. The author will also occasionally try zinc supplementation when prominent parakeratosis is described on histopathology. The author prefers zinc sulfate at 10mg/kg q 24h or zinc methionine or gluconate at 2mg/kg q 24h. Some cases may require concurrent glucocorticoid administration for optimal absorption and clinical efficacy. Zinc should be given with food to minimize gastrointestinal problems, ie vomiting and promote absorption.

Vitamin D Analogs

Vitamin D analogs, especially 1, 25-dihydroxyvitamin D3 (calcitrol) can be tried in severe seborrhea. Kwochka has evaluated it in cocker spaniel for treatment of idiopathic seborrhea. This agent was developed to maintain a positive impact of vitamin D on keratinization but minimize the hormonal influence of calcium ad phosphorus metabolism. Vitamin D analogs inhibit keratinocyte proliferation, induce terminal differentiation of keratinocytes and decrease immunological reactivity by reduced production of transcription of various cytokines and antigens presenting cells (Langerhans cells). It is dosed at 10 ng/kg q 24h. Cases need to monitored for changes in calcium metabolism with PTH, calcium and phosphorus levels checked weekly. Treatment responses may take 4 – 6 weeks to visualize.

Retinoids

Retinoids are natural or synthetic substances with vitamin A biologic activity. Initially vitamin A attracted attention because of its importance in the normal development and especially differentiation of keratinizing epithelial structures. Unfortunately its use was limited because of toxicity. The potential benefits and problems with toxicity led the pharmaceutical industry to try topical therapy and search for synthetic analogs of vitamin A that would offer wider margins of safety. Current research is directed towards finding retinoids that work at very specific retinoic acid receptor (RAR) class of nuclear receptors. Currently the major drawback with all the synthetic retinoids is their cost, which precludes their use in many cases.

Retinol and retinoic acid are the main active natural retinoids. The normal source is the dietary intake of retinyl esters (retinol esterfied with fatty acids) and beta-carotene, which are converted to the active forms. Retinyl esters come from animal fats with fish oils, and animal livers being the best sources. Therapy with beta-carotene and retinyl esters is much less toxic than retinol or retinoic acid because the body will regulate its conversion to retinol thereby avoiding excessive activity.

Retinoids function by entering cells and being transported to the nucleus where they interact with specific gene regulatory receptors. The natural vitamin A works at the cellular level by binding first to the cell membrane then transferring through the cellular cytoplasm by specific proteins; cellular retinol binding protein (CRBP) and cellular retinoic acid binding protein (CRABP). At the nucleus there is a transfer to other receptors that transfer the retinoids to their binding sites on DNA. The nuclear receptor(s) and retinoid complex then bind with specific regulatory regions in DNA called target sequences or hormone response elements and then alter gene transcription in a ligand dependent manner.

The potential for side effects from systemic retinoid toxicity is a major concern in humans but it appears that dogs are less sensitive to them. Retinoids are potent teratogens and for this reason human exposure is a concern and owners need to be warned and cautioned about proper handling. They should not be used in breeding animals. Other side effects to watch for include conjunctivitis, vomiting and diarrhea, keratitis sicca, pruritus, erythema of mucocutaneous junction and paws, leg and joint pain, anorexia and lethargy. Hypertriglyceridemia and hypercholesterolemia, which may be partly dietary controlled, have been seen but not associated with other clinical adverse signs. Elevated liver enzymes have also been seen in some cases. Skeletal cortical hyperostosis, periosteal calcification, and long bone demineralization are a concern but not reported in clinical dogs. Cats may have the same reactions though vomiting, diarrhea, anorexia and lethargy have been the most common recognized by the author. Etretinate appears to be tolerated better than isotretinoin and beta-carotene is the safest systemic form to give. Additional side effects of Etretinate include a sore mouth manifested by a reluctance to eat hard foods.

Vitamin A

In veterinary dermatology vitamin A has been recommended for a variety of keratinization disorders but primarily for the treatment of vitamin A responsive dermatosis. This is a syndrome described primarily in cocker spaniels and less in the schnauzer. These cases clinically appear similar to idiopathic cocker seborrhea. There are hyperkeratotic plaques that have a frond-like appearance, which represents numerous follicular plugs that lay on top of each other. This disease appears to be a variation of cocker seborrhea and can usually be separated by histopathology. The vitamin A responsive dermatosis will have marked follicular hyperkeratosis similar to phrynoderma in humans. These dogs will exhibit variable responses to 10,000 IU of vitamin A, once to twice a day. Others dose 1,000 IU/kg. Some generic forms are less effective and many authorities recommend Aquasol A. Vitamin A is also being recommended for sebaceous adenitis at the same dosages listed above. There is extreme variation to responses in sebaceous adenitis, with some cases exhibiting good responses and others no response at all.

Synthetic Retinoids

There are multiple synthetic retinoids available commercially with many others still being investigated. These are unique individual drugs and all retinoids are known in humans to have differing clinical effects and toxicities. The first synthetic retinoids introduced were for systemic use and were 13 cis-retinoic acid or isotretinoin (Accutane, Roche) and etretinate (Tegison, Roche), which is an analogue of retinoic acid ethyl ester. Etretinate is no longer marketed and has been replaced by acitretin (Soriatane).

Isotretinoin seems to have its greatest effect on sebaceous glands causing atrophy and alters the amount and content of the lipids in the secretions. This has been documented in humans and may be less effective in dogs though it still appears to be most effective in follicular and adnexal disorders versus epithelialization. Isotretinoin is helpful in the treatment of schnauzer comedone syndrome, congenital lamellar Ichthyosis, feline acne and sebaceous adenitis. The treatment doses ranges from .5 - 3mg/kg/q24h or divided q12h. Usually the drug should be given for at least one if not two months prior to evaluating the response. Some cases will respond faster. Accutane has received tremendous attention recently in humans due to the concern of marked depression and tendencies for patients taking the drug to commit suicide. It is difficult to prescribe in veterinary medicine due to the strong regulatory requirements.

Etretinate is indicated in disorders that are characterized by hyperproliferative keratinization and of less benefit in disorders of sebaceous glands. In primary idiopathic seborrhea of cocker spaniels 75% of the cases showed improvement. This improvement varies and shampooing is needed in some cases though at a much less frequency than prior to its use. It may also be helpful in English Springer spaniels, Irish setters, Golden retrievers and some mixed breed dogs. In contrast etretinate was ineffective in treating primary seborrhea in basset hounds and West Highland White Terriers (WHWT). I have seen it help some WHWTs once the Malassezia was controlled. It is helpful in about 50% of the cases of sebaceous adenitis. I have also used it to treat some forms of follicular dysplasia such as color dilution alopecia and seen improvement in the scaling, less secondary folliculitis and even partial hair growth. It has helped decrease the comedones in hairless breeds such as the Mexican hairless and Chinese crested. The dose of Etretinate most commonly used is 1 mg/kg.

Acitretin is an active metabolite of etretinate and is considered less toxic due to its relatively short half-life of two days versus 100 days. In human's acitretin is considered as efficacious as etretinate however this has not been documented in dogs and cats. It is more expensive than etretinate and at this time is being dosed the same or at one half the recommended dose of etretinate. Acitretin is not readily stored in fat therefore has less potential for post treatment teratogenicity. However in humans there is some conversion to etretinate leaving some though probably less risk. Acitretin studies in dogs are lacking and it is considered a replacement for etretinate. In addition the majority of studies done in animals were with etretinate so this discussion will cover etretinate but it is assumed that acitretin is an acceptable substitute at the same or ½ the dose.

Cyclosporine

Although not listed as one of its disease or clinical syndromes to treat, the author has found the use of cyclosporine to be helpful in some forms for primary keratinization defects. This most likely relates to its effects on down regulation of proinflammatory epidermal cytokines. When used it is dosed at standard dosing of 5mg/kg q 24h with and without ketoconazole depending upon the case.

Selected References

Rosenkrantz, WR. Practical Applications of Topical Therapy for Allergic, Infectious and Seborrheic disorders. Clinical Techniques in Small Animal Practice 21:106-117, 2006

Reme CA, Mondon A, Calmon, JP, et al: Efficacy of combined topical therapy with ant allergic shampoo and lotion for the control of signs associated with atopic dermatitis in dogs. ESVD and ACVD Vet Dermatol 15 (Suppl 1):20-40, 2004

Reme CA: Antimicrobial efficacy of tar and non-tar antiseborrheic shampoos in dogs in Hillier A, Foster AP and Kwochka, KW (eds): Advances in Veterinary Dermatology, vol 5, Oxford, UK, Blackwell Publishing Ltd, 2005, p 383.

Kwochka KW: Symptomatic topical therapy of scaling disorders, in Griffin CE, Kwochka KW, Mac Donald JM (eds): Current Veterinary Dermatology Mosby Year Book, St Louis, 1993, pp191-202

Kwochka KW: Advances in the management of canine scaling. Prod 3rd World Cong Vet Dermatol 1996 p 99.

Reme C: Antimicrobial efficacy of tar and non-tar antiseborrheic shampoos in dogs in Hillier A, Foster AP and Kwochka, KW (eds): Advances in Veterinary Dermatology, vol 5, Oxford, UK, Blackwell Publishing Ltd, 2005, pp 383-385

Scott DW, Miller WH, Griffin CE (eds): Muller and Kirk's Small Animal Dermatology, (ed 6), WB Saunders Company, Philadelphia 2001, pp 207-237

Carlotti DN, Bensignor E: Management of keratoseborrhoeic disorders. Eur J Comp Anim Pract, 12:123-133, 2002

Patterson S: Topical cyclosporine in sebaceous adenitis, in Hillier A, Foster and Kwochka, KW (eds): Advances in Veterinary Dermatology, vol 5, Oxford, UK, Blackwell Publishing Ltd, 2005, pp 382-383

Power HT, Ihrke PJ. Synthetic retinoids in veterinary dermatology, Vet Clin NT Am 20:1525, 1990

Peck GL, DiGiovanna JJ: The retinoids in Freedberg IM, Eisen AZ, Wolff K et al (eds) Fitzpatrick's Dermatology in General Medicine 5th ed., McGraw-Hill, New York, 1999 p2810-2820