Clinical Review: Topical Retinoids

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Clinical Review: Topical Retinoids

Clinical Uses

In view of their unique mechanism of action, topical retinoids are prescribed widely in dermatology for both indicated purposes and several worthwhile, evidence-based off-label uses. For seasoned clinicians, prescribing medications off label can be efficacious and even practical. A recent study evaluating off-label prescribing in treating dermatologic disease concluded that it is currently within the standard of care to use off-label prescriptions in treating dermatologic disease (Sugarman, Fleischer, & Feldman, 2002). However, practitioners who prescribe, dispense, or administer medications for an off-label use should have a full understanding of the rationale for such use, as well as any potential legal liabilities (Keltz, 2003) (see Table 2).
Acne Vulgaris

The cause of acne vulgaris is multifactorial and often requires multiple products to obtain optimum results. Clinicians should consider using a topical retinoid for first-line management for acne treatment (Wolf, 2002). It reverses thickening of the stratum corneum and the abnormal desquamation of keratinocytes (Verschoore et al., 1993). Acne therapy with retinoids can be frustrating in the beginning. An exacerbation of acne often occurs in the first 2 to 4 weeks of therapy as the follicular epithelium is loosening. Fortunately, by the end of the 2nd month, a significant improvement with the acne (Prystowsky, 2001) and remission of irritation is typically noted. To enhance compliance, the patient should be aware of these expected sequelae.

In patients with acne, sebum fills with pro-inflammatory lipids, creating a superb growth medium for bacteria (Millikan, 1999). Optimal therapy for inflammatory acne involves using topical retinoids or retinoid analogs combined with oral or topical antibacterials (Millikan, 2003). Since acne can flare during the initial phase of retinoid therapy, it has been recommended that an antimicrobial agent be used for the first few months of treatment only. This strategy combines speed of resolution and maintenance of remission from inflammatory and noninflammatory lesions with minimal exposure to antibiotic agents (Rizova et al., 2001). Regression of papulopustules has been noticed as early as 1 week after starting adapalene therapy (Rizova et al., 2001).

Benzoyl peroxide is a bactericidal agent that has been used in acne therapy for over 30 years. This product can often be irritating, drying, and occasionally allergenic. A reduction of drying side effects and an increased retinoid tolerance can be accomplished by advising morning use of benzoyl peroxide, reserving the retinoid for bedtime. Benzoyl peroxide can counteract with tretinoin, if used concurrently. Tretinoin gel microsphere (Retin-A Micro®) 0.1%, however, offers marked protection against tretinoin photo degradation, even in the presence of a strong oxidizing agent such as benzoyl peroxide (Nyirady, Lucas, Yusuf, Mignone, & Wisniewski, 2002). Adapalene demonstrates chemical stability in the presence of benzoyl peroxide. This combination can be used simultaneously without loss of efficacy (Berson, 1999).

It has been reported that tazarotene has greater comedolytic activity compared to other available topical retinoids (Guenther, 2002). A double-blind randomized trial was performed, comparing once-daily tazarotene 0.1% with once-daily tretinoin microsponge 0.1% gel. Tazarotene showed greater efficacy, comparable tolerability, and was a cost-effective alternative to tretinoin 0.1% microsponge gel (Leyden et al., 2002). A randomized trial evaluated an alternate-day application of tazarotene compared with once-daily adapalene use. This trial concluded that an alternate-day tazarotene regimen offers efficacy and suggests that this frequency can be beneficial even in those patients whose compliance may be less than optimal (Leyden, Lowe, Kakita, & Draelos, 2001).

A recent multicentered comparison trial of tazarotene 0.1% cream and adapalene 0.1% topical cream for treating facial acne vulgaris was reviewed (AAD, 2003). The study suggests that tazarotene may be superior to adapalene for reducing comedones. An impressive 77% of the tazarotene-treated patients achieved at least a 50% global improvement in acne, compared with 55% of adapalene-treated patients who achieved 50% improvement. Consideration, however, must be taken in the assessment of these results, for acne is multifactorial and it is rather difficult to evaluate 50 to 100 patients with the same manifestations (Peck, 2003).

A 12-week double blind study was conducted to evaluate the efficacy and safety of tretinoin microsphere 0.1% gel with adapalene 0.1% gel in the treatment of acne. Both drugs demonstrated similar efficacy in the resolution of acne, but tretinoin microsphere gel may result in a faster action in reducing comedones, compared to adapalene (Nyirady et al., 2001). Adapalene and all-trans retinoic acid (tretinoin) provide similar value for treating acne; however, adapalene is more chemically stable, less photolabile, and more lipophilic, enabling it to penetrate the follicles quickly (Prystowsky, 2001). Although tretinoin, tazarotene, and adapalene have all demonstrated efficacy in acne treatment, adapalene has shown the greatest tolerability (Wolf, 2002). Adapalene produces less erythema, intercellular edema, and hyperplasia of the epidermis when compared to all-trans retinoic acid (tretinoin) (Prystowsky, 2001). Perhaps this contributes to the increased efficacy of tretinoin and tazarotene for treating photodamage, when compared to adapalene.
Photoaging/Intrinsic Aging

The visible signs of aging skin, such as decreased clarity, progressive wrinkling, hyperpigmentation, roughness, and lack of tone are largely contributed to long-term UV exposure, often referred to "photodamage" (Weinstein et al., 1991). Tretinoin is recommended to help reverse photodamage. The first report documenting the use of tretinoin for photoaged skin was published in 1986. This landmark publication was conceived by Dr. Albert Klingman and colleagues after noting their well-controlled, middle-aged female acne patients were reluctant to discontinue tretinoin therapy, in view of a perceived improvement in fine lines and general skin appearance while using tretinoin (Klingman, Grove, Hirose, & Leyden, 1986). Improvement in skin wrinkling and roughness has been observed with long-term application of tretinoin. Dr. Elise Olsen and associates (Olsen et al., 1997) discovered that reducing the frequency of tretinoin 0.05% cream from once daily to 3 times per week maintains, and in some cases, possibly further enhances reduction of photodamage. They also observed that cessation of tretinoin therapy for 6 months, however, resulted in some reversal of the beneficial effects seen after 48 weeks of treatment.

Topical all-trans-retinoic acid (tretinoin) protects the skin against damage from UVA and UVB rays (Francz, Conrad, & Biesalski, 1998). Tretinoin facilitates the ability to prevent collagen loss and stimulate new collagen formation within the papillary dermis of sun-exposed skin (Griffiths, 2001). In a multicenter study, patients treated with topical tretinoin appeared to develop an increased awareness of the adverse effects of sun exposure and increased motivation to employ sunscreens and sun avoidance as additional means of preventing skin damage (Weinstein et al., 1991).

When compared to superficial chemical peels, retinoid-based topical agents have been known to provide analogous and possibly superior results. Indefinite use, however, is needed to maintain efficacy (Baumann, 2003). Currently, tretinoin is often used before and after skin resurfacing and adjunctively with other cosmetic procedures to enhance and maintain results. To prepare the stratum corneum, tretinoin is often applied 4 to 6 weeks prior to a chemical peel. Preoperative treatment with tretinoin helps to evaluate patient compliance and assess how the patient's skin will respond postoperatively (Alster, 2003).

A 12-month, multicenter, randomized trial evaluating the efficacy and safety of 0.1% tazarotene cream for the treatment of photodamage revealed significantly reduced abundant signs of photodamage. Clinically relevant reductions in fine wrinkling, mottled hyperpigmentation, lentigines, elastosis, pore size, irregular depigmentation, tactile roughness, coarse wrinkling, and overall integrated assessment of photodamage were more effective than vehicle. Additional efficacy may be attainable with prolonged treatment, for efficacy had not plateaued after 12 months of therapy. Plasma levels of tazarotenic acid remained below those of endogenous retinoids, and no systemic accumulation of drug was evident (Phillips et al., 2002).

Goldfarb (2000) evaluated adapalene (Differin®) for treating photodamage (actinic keratosis and lentigines). He concluded that adapalene was tolerated well and is a drug we should keep in mind as a second-tier therapy for patients who are not progressing well with standard therapy.

Though usually temporary, retinoid irritation can lead to noncompliance. Rather than resorting to using unregulated, unpredictable over-the-counter products, an alternative 0.02% low-dose, oil-in-water formulation of tretinoin is now available by prescription. A 52-week clinical trial concluded safety and efficacy of 0.02% tretinoin cream for treating photodamage. The most evident outcome, in this trial, revealed improvements in fine wrinkling. Results were maintained with long-term use. Discontinuation of therapy, however, showed a gradual beneficial loss. Mild skin irritation was common, nevertheless generally well tolerated (Nyirady, Lehmann, & Nordin, 2003).
Psoriasis

The key pathologic components occurring in psoriasis are epidermal hyperproliferation and parakeratosis (Verschoore et al., 1993). Tazarotene was developed as an antipsoriatic drug in view of the therapeutic results of minimizing scaling and plaque thickness (Prystowsky, 2001). In psoriasis, tazarotene normalizes keratinocyte differentiation, reverses keratinocyte hyperproliferation, and has better anti-inflammatory effects compared to other topical retinoids (Guenther, 2002). To enhance patient compliance, achieve optimal results, and ease the cutaneous irritation, adjunctive therapy with medium to high-potency topical steroids may be indicated. Improved efficacy has been noted with tazarotene coupled with a vitamin D3 analog (Dovonex®). The combination of calcipotriol and tazarotene is comparable in efficacy to clobetasol. Using this combination prudently could minimize the long-term adverse effects of topical steroids (Feldman & Hu, 2003). Tazarotene is often used as adjunctive therapy with a topical corticosteroid or phototherapy for treating psoriasis (Guenther, 2002).
Actinic keratosis and actinic lentigines

Topical retinoids are often used off-label for treating actinic keratosis (AKs/pre-cancers) and actinic lentigines (freckles) in view of the ability to decrease melanogenesis, its antiproliferative effect, antipromoter effect, and prodifferentiation effect (Goldfarb, 2000). Although the actual number of solar lentigines may not change with adapalene, improvement of discrete pigmentation and significant color reduction occurs (Goldfarb, 2000). Topical tretinoin decreases the number of AKs on the face by approximately 50% when used as monotherapy over a minimum of 6 months (Prystowsky, 2001). Topical tretinoin effectively treats photodamage. Human studies have found tretinoin to be noncarcinogenic and can prevent the formation of UV-induced lesions (Baumann, 2003). In view of topical tretinoin's ability to normalize the differentiation of dysplastic epithelium in AKs, it can be considered for chemoprevention in patients at high risk of basal or squamous cell carcinomas (Prystowsky, 2001). Retinoids provide an alternative for patients with significant photodamage who have no objections to off-label usage, who might be at risk for AKs, and who are looking for a gentle therapy (Goldfarb, 2000).

Transplant recipients are a unique subset of people for whom the sequelae of sun damage are even more hazardous. Within 5 years of immunosuppression, 40% of transplant recipients experience premalignant skin tumors such as AKs and Bowen's disease, as well as skin cancers such as squamous cell carcinoma (SCC) and basal cell carcinomas (Stockfleth, Ulrich, Meyer, & Christophers, 2002). Early, preventative treatment could halt the development of invasive SCC (Euvrard, 2000). Topical retinoids can provide an often-favorable alternative to cryotherapy, and other destructive regimens, in persons with multiple lesions (Stockfleth et al., 2002).
Premalignant Oral Lesions

Chemopreventative treatment with retinoids has been studied for patients with oropharyngeal carcinoma. The mechanism of action of vitamin A modulates growth and differentiation of cells, and vitamin A deficiency enhances susceptibility to carcinogenesis. Side effects of topical use have been minimal. Suppression of oral leukoplakias has been noted with the direct application of retinoic acid. Treatment may be justified in those patients with recurrent and persistent lesions that may otherwise progress (Gorsky & Epstein, 2002).
Rosacea

Rosacea is a common, multifactorial, multiphasic, inflammatory skin disease in which chronic flushing and blushing results in permanently dilated blood vessels (telangiectasias). Although there is no known cure, rosacea can be managed and controlled with medication (Bergfeld, 1999). Many first-line treatments have been refractory to this condition. In a comparison study regarding the efficacy of topical tretinoin and low-dose oral isotretinoin in rosacea, low-dose oral isotretinoin and topical tretinoin cream appear to be beneficial in treating severe or recalcitrant rosacea (Ertl, Levine, & Klingman, 1994). Systemic medications are not without risk. If possible, the risk of systemic side effects should be minimized. Recent clinical research suggests that topical tretinoin minimizes the manifestations of papular-pustular rosacea within a relatively short treatment duration (Bergfeld, 1999). Topical retinoids have often been considered controversial as a treatment for rosacea in view of the associated increased redness, burning, and peeling of the skin. This irritation, however, has been typically temporary. According to a recent literature review, in addition to the traditional avoidance of triggers along with topical and oral antibiotic therapy, current effective treatment now also includes both topical and oral retinoid therapy, topical vitamin C therapy, and cosmetic surgery (Cohen & Tiemstra, 2002).
Verruca

Human papillomavirus (HPV) infections are widespread and cause a plethora of benign clinical lesions on the skin and mucous membranes (Fitzpatrick et al., 1997). Topical retinoic acid has shown moderate, favorable results for treating verruca plantaris and verruca plana (Verschoore, 1993). Topical tretinoin is often beneficial when treating facial verruca. As dermatology practitioners, we have noticed that treatment of facial verruca with tretinoin is less irritative and is comparatively efficacious to imiquimod (Aldara®).
Hypertrophic Scars, Keloids, Acne Scars, and Striae

Increased epidermal proliferation and new collagen formation contribute to the improvement of hypertrophic scars, keloids, and acne scars (Verschoore, 1993). In an open-label, multicenter, prospective study, topical tretinoin 0.1% significantly improved the clinical appearance of pregnancy-induced stretch marks (Rangel, Arias, Garcia, & Lopez-Padilla, 2001). Striae originating from weight gain or endocrine-related disorders could likewise benefit from the use of topical retinoid therapy.
Cutaneous Lichen Planus

Lichen planus (LP) is an acute or chronic inflammatory dermatosis involving skin and/or mucous membranes. Topical retinoic acid (tretinoin) is an effective maintenance therapy for cutaneous lichen planus and can contribute to preventing recurrence (Verschoore, 1993). This is most likely due to the increased epidermal proliferation and collagen-forming activities of topical retinoids. The rationale for using tazarotene in oral lichen planus (OLP) is its regulatory action on the growth and differentiation of keratinocytes and on inflammation (Petruzzi et al., 2002). Compared to control, topical tazarotene showed a significant reduction of lesions and remote transitory side effects (burning sensations and taste abnormalities). Topical tazarotene may provide a valuable therapeutic tool in treating hyperkeratotic oral lichen planus (Petruzzi et al., 2002).
Melasma

Melasma is an acquired light or dark-brown hyperpigmentation that rapidly evolves. It is limited to sun-exposed areas, most often on the face. Genetic predisposition, solar UV radiation, hormones, and several drugs have been identified as notable factors in the pathogenesis of melasma. Treatment consists of sun protection, 4% hydroquinone cream twice daily, with adjunctive tretinoin 0.05% to 0.1% cream at bedtime. Sunbathing is contraindicated, since this can result in the reversal of months of topical therapy. Tretinoin is reasonably well tolerated and increases the efficacy of hydroquinone (Pathak, Fitzpatrick, & Kraus, 1986). Patients with dermal melasma do not respond well to hydroquinone and tretinoin. The best therapy results are obtained in those presenting with epidermal or mixed melasma (Pathak et al., 1986). Wood's lamp examination is helpful to differentiate melasma involvement in skin phototypes I to IV, and accentuates epidermal melasma, not dermal melasma. It is of no value in skin phototypes V and VI (McMichael, 2003).
Darier's Disease

Darier's disease is a rare, noncurable, genodermatosis affecting approximately 1 in 55,000 people (English, 2000). This disease is often associated with disfiguring, symmetrical, generalized pruritic cutaneous eruptions occurring in the seborrheic areas that can be malodorous, often detrimental to the self-esteem and quality of life of these individuals. Retinoids (oral and topical) are effective for treating Darier's disease; however, the mechanism of action is not known (English, 2000). Oral retinoids are the most effective treatment, but are associated with troublesome side effects (Cooper & Burge, 2003). Case studies have reported favorable success regarding the use of tazarotene gel and adapalene gel for this disorder (English, 2000).
Wound Healing

Pretreatment of skin with all-trans retinoic acid (tretinoin) can enhance wound healing. Histological effects of tretinoin demonstrate compaction of the stratum corneum, epidermal acanthosis with correction of atypia, an increase in small vessels, and increased cellularity in the upper dermis. Tretinoin dramatically accelerates wound healing in photodamaged skin (Popp, Klingman, & Stoudemayer, 1995). Pretreatment of skin with topical tretinoin may be beneficial in reducing healing times of patients undergoing electroepilation (Anthony, Miller, & Dinehart, 1991). Pretreatment with topical all-trans retinoic acid (tretinoin) has also reversed impaired wound healing in genetically diabetic mice (Kitano, Yoshimura, Uchida, Sato, & Harii, 2001).

The employment of topical retinoids in wound healing is flourishing. Retinoic acid reverses the inhibitory effects of glucocorticoids on wound healing and expedites the formation of healthy granulation tissue. Pretreatment with tretinoin prior to epidermal injury, such as chemical peeling and dermabrasion, accelerates wound healing. Short-contact tretinoin therapy is a novel modality for treating chronic ulcers and stimulating granulation tissue formation (Paquette, Badiavas, & Falanga, 2001). A comparison of tretinoin, adapalene, and collagenase in an experimental model of wound healing concluded that tretinoin and adapalene contributed to the wound healing process resulting in an enhancement of collagen production, angiogenesis, and granulation tissue formation (Basak et al., 2002).
Granular Parakeratosis

Granular parakeratosis is a rare, acquired dermatosis characterized by keratotic papules, located in intertriginous regions. A recent case report demonstrated rapid clearance of such lesions to the axilla, with topical administration of tretinoin (Brown & Heilman, 2002).
Multiple Miliary Osteoma Cutis

This is a condition that consists of primary extra-skeletal bone formation that arises within the skin. Local application of tretinoin decreases the number of papules over the face in those patients suffering with this condition. Response time varies from a few weeks to 6 months. Tretinoin cream can be considered in treating multiple miliary osteoma cutis of the face, especially when dealing with small and superficial lesions (Cohen, Chetov, Cagnano, Naimer, & Vardy, 2001).
Alopecia Areata

Patients with alopecia areata can have patchy or confluent hair loss on the scalp and/or body. Treatment options are tailored to the severity of the disease, including either irritants/immunogens, or local/systemic immunosuppressives (Olsen, 2003). Combination therapy is often used. Beneficial treatment outcomes, using topical tretinoin for hair growth disorders, have been reported (Hass & Arndt, 1986). Safety and efficacy of 0.05% tretinoin and adjunctive intra-lesional triamcinolone was evaluated for treating alopecia areata. Topical tretinoin appeared to enhance the hair growth producing effect of the intralesional triamcinolone. Tretinoin helps to normalize cell differentiation, and the familiar retinoid dermatitis may contribute to the stimulation of hair growth by creating an immune response. Topical tretinoin coupled with topical minoxidil has also showed promising results for treating alopecia areata.
Keratosis Pilaris (KP)

KP is the most common, benign follicular keratosis. With KP, an overgrowth of protein in the skin, known as keratin, becomes clogged within hair follicles, creating a rough, bumpy appearance to the skin. This harmless, yet sometimes annoying condition can be managed with various topical regimens that promote hydration and remove excess keratin (for example, Lac-Hydrin®, AmLactin®, and Carmol®). The application of salicylic acid cream can inhibit the formation of plugged follicles. Tretinoin effectively reduces adherence among keratinized cells (Crowe & Escobar, 2003). To enhance compliance, it is recommended to start with a low-dose and frequency of tretinoin and gradually increase, as tolerated. Retinoid-associated dermatitis can occur quickly. Improvement of this condition is remarkably gradual and cessation of therapy can lead to recurrence.
Acanthosis Nigricans (AN)

AN has been considered a prognostic indicator for the onset of acquired, type II diabetes. Most cases are associated with obesity, insulin resistance, and hyperinsulinemia. AN has occasionally been linked to an underlying malignancy (Houpt & Cruz, 2003). Topical retinoids have been used, with varying degrees of success. The synergistic combination of topical tretinoin 0.05% at bedtime and 12% ammonium lactate (Lac-Hydrin®) lotion twice daily has shown a 85% to 95% improvement of AN presenting on the neck, associated with obesity (Blobstein, 2003).