Therapeutic Advances in Dermatology

The authors round up the current options for treating skin conditions that plague many patients, including herpes, acne, rosacea, actinic keratoses, warts, hair loss, hives, and other problems.

By Stephen M. Schleicher, MD, Lawrence A. Schiffman, DO, and Richard F. Cordova, DO

Dermatologic therapy continues to evolve in many interesting ways. Some new treatment modalities offer only a limited advantage over standard therapies, but others represent real breakthroughs. In this article, we will review several common skin conditions in light of recently introduced therapeutic options.
 

ACNE AND ROSACEA

Azelaic acid in a cream base (Azelex/Finevin) was introduced for the treatment of mild to moderate acne in 1996. The compound is nontoxic, antibacterial, and usually well tolerated. Acne responds slowly to this therapy, but the medication may be used safely on a long-term basis. The compound possesses skin-bleaching properties and is useful in the treatment of dark-skinned individuals with post-inflammatory macules secondary to acne lesions. A gel form of this drug (Finacea) was approved this year for the treatment of papules and pustules associated with rosacea, the first new topical therapy for this condition in several years.

Because of their anti-inflammatory properties, sulfur-containing preparations have been used for decades to treat acne and rosacea. The most recently released sulfur-derived preparations include Klaron and Plexion lotions, Clenia cream, Rosula gel (which also contains urea), Avar gel (tinted green to help mask erythema), and Plexion, Rosanil, Clenia, Rosula, and Avar washes. All have very low irritancy potential and may prove useful in the topical treatment of mild acne and rosacea.

Tazarotene cream (Tazorac) was approved for the treatment of acne in 2001. (The product is also available as a gel). The drug is a retinoid related to adapalene (Differin) and tretinoin (Retin-A, Avita). Retinoids are most useful in the treatment of comedonal acne. They all have the potential to cause irritation, especially in fair-skinned individuals. Because of this, it has been proposed that Tazorac be used for only brief intervals—for example, one half-hour nightly. Retin-A Micro 0.04%, which was released in 2002, may prove less irritating than other forms of Retin-A.

Isotretinoin (Accutane) has been used for more than two decades to treat cystic acne. A generic form (Amnesteen) was approved by the FDA in 2002; another generic form (Sotret) was approved this year. Isotretinoin is teratogenic and requires careful patient monitoring in females of childbearing age. The drug has been linked to mood changes, depression, and suicide, which received considerable media attention. However, a causal relationship to psychiatric disorders remains controversial and far from certain.

The combination of clindamycin and benzoyl peroxide in a gel form was first marketed as Benzaclin in 2001. The product is effective in the treatment of inflammatory acne and is probably more effective than either ingredient used as monotherapy. This year a similarly formulated product, called Duac Topical Gel, has been introduced.

Because of a more negative side-effect profile associated with minocycline, including unsightly skin pigmentation and the potential for elevated liver enzymes, doxycycline usage for acne and rosacea is gaining in popularity. The usual dose is 50 to 100 mg twice daily. A 20-mg form is available as Periostat; twice-daily dosing with this drug is currently being investigated as therapy for low-grade acne and rosacea.

Lasers have been used for years with variable results to mitigate the unfortunate sequelae of acne—namely, scars. Most recently, lasers and other light sources have been utilized to treat active acne. Whether these treatments will prove to be viable options or just expensive hype will be determined by the outcomes of larger clinical studies. However, lasers are quite useful for reducing the telangiectasias associated with rosacea.
 

ACTINIC KERATOSES

Actinic keratoses are induced by chronic sun exposure and appear most commonly on the hands and face of fair-skinned persons. A small percentage will evolve into squamous cell carcinomas. Individual lesions respond best to liquid nitrogen cryosurgery or curettage. When multiple lesions are present, chemosurgical destruction utilizing topical fluorouracil is a therapeutic option. This treatment may destroy subclinical lesions. The major drawback is irritation of the treated areas, which may be marked and may persist for more than two weeks after therapy is discontinued. Topical Efudex and Fluoreplex are utilized as twice-daily therapy; in 2001, Carac cream was approved by the FDA for daily use. Therapy is best continued for a full month.

Aminolevulinic acid (Levulan Kerastick) is approved by the FDA to treat nonhyperkeratotic actinic keratoses of the face and scalp. The treatment uses a porphyrin-based photosensitizer that is applied to visible lesions and then activated one day later with blue light. Many patients experience transient burning and stinging. However, the cure rate does not appear to be higher than with liquid nitrogen, and the procedure entails greater expense and patient inconvenience.

Solaraze gel, the topical form of the nonsteroidal anti-inflammatory drug diclofenac, was approved for the treatment of actinic keratoses by the FDA in 2000. The percentage of lesions cleared with this therapy is disappointing (only 40% resolution after four months of therapy); it is surpassed by more traditional treatments.

Imiquimod (Aldara), a topical immunostimulant approved by the FDA for treatment of genital warts, is also being used to treat actinic keratoses. As with fluorouracil, marked inflammation may develop. Additional clinical studies are needed to evaluate dose schedule and response rates.

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ECZEMA AND ATOPIC DERMATITIS

In 2000, the FDA approved tacrolimus ointment (Protopic) for the treatment of eczema. This medication, available in a 0.1% or 0.03% concentration, acts as a topical immune suppressant. Pimecrolimus cream (Elidel), which works in a similar manner, was approved in 2001. Both drugs may cause transient stinging when first applied. Protopic and Elidel are best utilized as maintenance therapy rather than initial therapy for eczema. Both appear to be safe to use for long periods of time, even on the face and intertriginous areas. Both are approved for use in children aged two years and older. Systemic absorption of these topical immunomodulators is negligible. Unlike fluorinated topical steroids, neither will induce cutaneous atrophy.

A comprehensive review published in 2000, funded by Great Britain's department of health, analyzed scores of randomized controlled studies and affirmed that topical steroids are justified as first-line therapy in all patients with eczema. (This study predates topical immunomodulator therapy.) A 2002 study of children with mild to moderate atopic dermatitis (see photo below) published in the British Medical Journal found that short-burst therapy with the potent topical steroid betamethasone valerate was just as effective as prolonged use of the weak topical steroid 1% hydrocortisone. A 1999 study published in the British Journal of Dermatology found that fluticasone propionate cream (Cutivate) was safe and effective in acute and longer-term therapy of adults with moderate to severe atopic dermatitis.

A small percentage of eczema cases do not respond adequately to topical therapies. Such cases may require periodic administration of oral or intramuscular steroids. Steroid-sparing immunosuppressants include cyclosporine and methotrexate.

Atopic dermatitis   Female pattern alopecia   Male pattern alopecia

HAIR GROWTH AND EXCESS HAIR

In 1988, minoxidil (Rogaine) became the first drug approved for use as treatment for male pattern baldness. The product is now available over-the-counter as a 2% solution, which is called Rogaine for Women. Extra Strength Rogaine contains a 5% solution and is marketed for men. The effects of minoxidil are dose dependent; the higher percentage is more effective. Women with hair thinning of the female pattern type (see photo above) can safely use the 5% solution of minoxidil, but they should be advised to stop using it if excess facial hair develops.

Finasteride 1 mg (Propecia) was approved for the treatment of male pattern alopecia (see photo above) in 1997. The drug works by inhibiting the conversion of testosterone to dihydrotestosterone. Side effects are minimal. Studies involving postmenopausal women with alopecia have been disappointing. A five-year follow-up study of men published in 2002 documented that Propecia was safe for chronic use and slowed the progression of hair loss over time. Combined use of both Propecia and Rogaine is being investigated.

Alopecia areata is a disease characterized by circumscribed patches of hair loss. Infrequently, progression to total scalp hair loss (alopecia totalis) occurs. The etiology is believed to be related to immune dysfunction. Standard therapy for the localized form of alopecia areata is steroids, used either topically or intralesionally, or both. Therapeutic responses to Elidel, Protopic, and Aldara have recently been reported, but larger studies are needed to evaluate efficacy.

Eflornithine (Vaniqa), the first prescription topical therapy approved to decrease facial hair growth in women, became available in 2000. Results usually take two months to become apparent; approximately 50% of users respond to therapy.

Several different lasers and pulsed light devices are used to remove hair. Ideal candidates are light-skinned individuals with darker hair. In 1998, the FDA allowed some manufacturers to claim "permanent reduction" (as opposed to "permanent removal") of hair follicles. Although some patients do experience permanent reduction, others do not and require repeat treatments.
 

HEAD LICE

Head lice and their eggs, called nits, are visible to the naked eye. First-line therapy consists of the use of over-the-counter shampoos containing either a pyrethrin (Rid) or a permethrin (Nix). A second treatment 7 to 10 days later is recommended. Resistance to these formulations appears to be on the rise, and in 1999 the FDA reapproved Ovide lotion, a highly effective prescription product containing malathion. This compound is applied to the scalp and left on overnight.
 

HERPES SIMPLEX AND HERPES ZOSTER

Acyclovir (Zovirax), famciclovir (Famvir), and valacyclovir (Valtrex) are the mainstays of therapy for herpes simplex and herpes zoster (see photos below). In 2001, the FDA approved a shorter dosage schedule for the treatment of recurrent genital herpes with Valtrex. The previously recommended schedule of 500 mg twice daily for five days was changed to three days. According to data presented in 2002 at the Interscience Conference on Antimicrobial Agents and Chemotherapy, once-daily Valtrex suppression therapy significantly reduced viral shedding and transmission of symptomatic genital herpes to a noninfected partner. In 2002, the FDA approved 2 gm of Valtrex twice daily for one day as therapy for cold sores.

Herpes simplex     Herpes zoster

A study published in 2000 in the Archives of Family Medicine compared Valtrex and Famvir for the treatment of herpes zoster and found them therapeutically equivalent in terms of both rate of spontaneous healing and pain relief. However, no single treatment to date has proved uniformly successful for the treatment of postherpetic neuralgia.

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HIVES

Most cases of urticaria (see photo below) promptly clear when the offending agent, such as ampicillin or cashews, is withdrawn. Chronic urticaria, which is hives persisting for more than six weeks, is more problematic. The majority of these cases are of an unknown etiology and treatment is difficult. Nonsedating antihistamines, such as loratadine (Claritin), desloratadine (Clarinex), cetirizine (Zyrtec), and fexofenadine (Allegra), are the mainstays of therapy. In 2002, loratadine became an over-the-counter medication; the H₂ receptor antagonist cimetidine (Tagamet) is often added. A short course of oral prednisone may prove helpful. Numerous medications, ranging from asulfadine to valacyclovir, have been reported to be beneficial in individual case reports or small series, but no controlled studies have been conducted.

Urticaria    Onychomycosis

MELASMA

Melasma manifests as mottled hyperpigmented patches on the face. Females are most often affected, and contributing factors include sun exposure, pregnancy, and oral contraceptives. The topical cream Tri-Luma became available to treat melasma in 2002. This medication contains a bleaching agent (hydroquinone), tretinoin (analogous to Retin-A), and a topical steroid. Continuous use should not exceed eight weeks, and daily application of a sunscreen is advised.
 

ONYCHOMYCOSIS

Invasion of the nail plate by a fungus or yeast, or both, is called onychomycosis (see photo above). Traditional therapy entailed many months of daily oral griseofulvin, which yielded only a low cure rate. Higher cure rates utilizing shorter treatment times can be achieved with either terbinafine (Lamisil) or itraconazole (Sporanox); most published studies demonstrate greater efficacy with the former. Ciclopirox (Penlac) is a lacquer approved in 1999 for the topical treatment of fingernail and toenail fungus. It is widely used by podiatrists as therapy once the infected nails are pared. Cure rates utilizing Penlac are much lower than those achieved with oral therapy.
 

PSORIASIS

Psoriasis (see photo below) is a chronic skin disorder characterized by plaque formation. The scalp, elbows, and knees are most commonly affected. More severe cases may involve a significant percentage of body surface. Some individuals develop an associated arthritis. The mainstay of treatment is topical steroids, often combined with the topical vitamin D analogue calcipotriene (Dovenex), the topical vitamin A analogue tazarotene (Tazorac), or tar preparations. A formulation combining both calcipotriene and the steroid betamethasone dipropionate was launched in Canada in February 2002 and has been submitted to the FDA for release in the United States. A potent topical steroid containing clobetasol in a novel foam formulation, called Olux, already approved for scalp psoriasis, received FDA approval in 2002 for short-term use on other body areas, excluding the face and intertriginous regions.

Psoriasis

Some cases of psoriasis require systemic therapy for adequate control. Oral psoralen plus ultraviolet light (PUVA), methotrexate, cyclosporin (Neoral), and acitretin (Soriatane) are the most commonly used systemic therapies. All require careful patient monitoring. Narrow-band UVB may supplant PUVA as phototherapy. While certain lasers were recently approved by the FDA to treat psoriatic plaques, the practicality of such therapy is questionable.

The underlying etiology of psoriasis involves immune dysregulation, which induces the hallmark of the disease, epidermal hyperproliferation in the form of scales and plaques. Several new therapies for psoriasis specifically target the immune system. In 2003, alefacept (Amiveve) became the first "biologic" approved by the FDA to treat psoriasis. This drug is administered by intravenous (IV) or intramuscular injection, and it works by blocking certain subsets of activated T cells. Treatment consists of 12 weekly injections.

Etanercept (Enbrel) was approved in January 2002 for the treatment of psoriatic arthritis and should soon receive approval for the treatment of psoriatic skin lesions as well. The mechanism of action involves inhibition of tumor necrosis factor-alpha (TNF-alpha). The medication is given by subcutaneous injection twice weekly. Efalizumab (Raptiva) is an antibody that prevents activated T cells from entering the skin; it is given by subcutaneous injection once weekly. This drug is awaiting FDA approval. Infliximab (Remicade) was approved in 1998 for the treatment of Crohn's disease and one year later for the treatment of rheumatoid arthritis. The drug binds to TNF-alpha and is given by IV infusion. Approval from the FDA for treatment of psoriasis is expected this year.

The new biologics are expensive and cannot be taken orally. However, they do not require continuous administration and appear to have a higher safety profile than systemic therapies.
 

SCABIES

Scabies (see photo below) is an intensely pruritic infestation that is spread by close personal contact. Most cases are easily treated with topical use of 5% permethrin cream. However, such treatment is somewhat messy and requires overnight skin contact. Compliance in certain populations, such as nursing home residents, is an issue, as is the emergence of resistance. In 1995, an article was published in the New England Journal of Medicine documenting the efficacy of a single oral dose of the antiparasitic agent ivermectin as monotherapy for scabies. Subsequent clinical studies and the authors' personal experience confirm the usefulness of this treatment. As with permethrin, some clinicians advocate a second dose in 7 to 10 days.

Scabies    Scars and keloids

SCARS AND KELOIDS

Newer treatments for localized scars and keloids (see photo above) include topical application of silicon-based sheeting and Mederma, an over-the-counter botanical-based gel that the manufacturer claims helps scars appear softer and smoother. These agents, although safe to use, may serve merely to hydrate. More objective studies are needed to document clinical efficacy. The topical immune stimulant Aldara may help to prevent keloids following surgical excisions, although here too randomized controlled studies are lacking.

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SEBORRHEIC DERMATITIS

Seborrheic dermatitis is a frequently encountered disorder characterized by redness and scaling. Areas of the face most commonly involved include the forehead, ears, eyebrows, and nasolabial folds. The condition usually responds quite well to low-potency topical steroids, but its chronic nature often necessitates long-term therapy. Some cases respond to ketoconazole cream (Nizoral). Separate studies presented at the World Congress of Dermatology in 2002 indicate a favorable response to both ciclopiroxolamine cream (Loprox) and Protopic ointment.
 

TINEA CAPITIS

Tinea capitis (see photo below), or scalp ringworm, is most common in African-American children. All clinically apparent cases should be treated with oral antifungal therapy. The mainstay of therapy has been griseofulvin, administered for six to eight weeks. Several newer antimycotic agents have proved to be safe and effective, including Lamisil, Sporanox, and Diflucan (fluconazole). Compliance is enhanced with these medications because of a shorter duration of therapy. However, none of the newer agents is as yet approved by the FDA to treat tinea capitis.

Tinea capitis

VITILIGO

Vitiligo (see photo below) is a common disorder that manifests as depigmented patches of skin. Its etiology appears to be autoimmune in nature. Superpotent topical steroids, such as Temovate or Ultravate, or topical immunosuppressants, such as Elidel cream or Protopic ointment, or both, may induce repigmentation. Use of narrow-band UVB light therapy and certain lasers has also recently been demonstrated to be effective in selected cases, but such therapy is not widely available. A more traditional therapy is PUVA; one drawback, however, is that multiple treatment sessions are required, along with the specialized light source. As a rule, the earlier any therapy is started for vitiligo, the greater the chance of successful repigmentation.

Vitiligo     Warts

WARTS AND WRINKLES

There is not much that is new in therapies for the common wart. Aldara, which is used to treat external genital warts, is worth a try for persistent verrucae (see photo above) elsewhere. Studies utilizing cimetidine as oral therapy for warts have produced mixed results. Various other treatments have been advocated to eradicate warts, one of the latest being the application of duct tape, which was reported to be effective in a 2002 report.

Tretinoin (Renova) is the first topical cream approved by the FDA to "reduce fine wrinkling associated with chronic sun exposure and the natural aging process." The product is identical in chemical structure to Retin-A. It was released initially as a 0.05% cream, and later in a 0.02% strength that is purportedly less irritating. In 2002, Avage cream 0.1% was approved by the FDA for use as "an adjunctive agent in the mitigation of facial fine wrinkling, facial mottled hyper- and hypopigmentation, and benign facial lentigines." This product is identical to Tazorac cream 0.1%. As with Renova, results usually take many months to become visibly apparent.

Botulinum toxin (Botox) was approved by the FDA in 2002 for the temporary amelioration of forehead and glabella lines. Results are dramatic and side effects minimal and temporary. The toxin also works quite well to reduce or eliminate crow's-feet (periocular wrinkles). Botox is administered by injection; effects last three to four months.

The gold standard for injectable filling agents is represented by Zyderm and Zyplast. Both are derived from bovine collagen and require intradermal allergy testing prior to administration. Uses include elevation of the nasolabial folds, lip augmentation, and scar repair. This year, Cosmoderm and Cosmoplast were made available; these contain laboratory-derived collagen and do not require skin testing prior to use. Within the next two years, the FDA is expected to approve several additional contour correction agents, including Artefill, Dermologen, Hylaform, Perlane, Radiance, and Restylane.

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