Topical retinoids are singularly important agents in the treatment of acne vulgaris. Any molecule having a biological effect through the binding and activation of retinoid receptors is considered a retinoid (1). This class of medications includes vitamin A and all synthesized molecules that are derived from it (1). By influencing DNA transcription, retinoids can modify cellular growth and differentiation, immunomodulation, and tumor promotion. In turn, they improve acne vulgaris by inhibiting microcomedone formation, diminishing the number of mature come- dones as well as inflammatory lesions, and normalizing follicular epithelium matu- ration and desquamation (2).
Three generations of retinoids exist. First-generation topical retinoids include vitamin A and its derivatives retinaldehyde, all-trans-retinoic acid (all-trans-RA) or tretinoin, and 13-cis-retinoic acid (13-cis-RA) or isotretinoin (3). The second gen- eration retinoids comprise synthetic analogs where one aspect of the basic vitamin A structure has been changed, such as etretinate and acitretin, though no topical forms of these forms exist (3). Third-generation retinoids have significant modifi- cation of the original molecule, such as adapalene, tazarotene, arotinoid, arotinoid methyl sulfone, and arotinoid ethyl ester (3). Presently, there are seven topical reti- noids: tretinoin, adapalene, tazarotene, topical isotretinoin, motretinide, retinalde- hyde, and b-retinoyl glucuronide (3). Only all-trans-RA, adapalene, and tazarotene are available in the United States and are discussed in the text that follows.
Absorption of topical medications occurs transepidermally or transfollicularly, influenced by the size of the particles involved (4). Molecules 3 to 10 mm in diameter penetrate the follicular ducts, making this size the ideal target size for acne therapy (4). Particles larger than 10 mm become trapped on the skin surface, whereas par- ticles less than 3 mm disperse over the stratum corneum and hair follicles and are, therefore, less efficacious (4).
MECHANISM OF ACTION
Topical retinoids act to clear and prevent the formation of the microcomedo, the precursor to acneiform lesions. The microcomedo is formed from the occlusion of the follicular ostium by the androgen-induced production of sebum and the
accumulation of stratum corneum cells (5). In normal skin, the corneocytes of the hair follicle’s infrainfundibular region are small and form a noncontinuous, inco- herent layer of cells that easily desquamate individually into the follicular canal (1,2,6). They then travel to the surface of the skin through the secretion of lipid- rich sebum (6). In contrast, the follicular epithelium of the microcomedo demon- strates abnormal, hyperactive keratinization, resulting in hypergranulosis and hyperkeratosis (2,5). Corneocytes are more cohesive and less able to migrate to the skin surface and instead become lodged within the follicle, occluding the expul- sion of sebum, distending the follicular ostia, and thus forming the comedo (1,6). The anaerobic environment created therein favors the proliferation of Proprinibac- terium acnes (1,6), which subsequently creates an inflammatory response by secret- ing lipase, releasing chemotactic factors, and recruiting polymorphonuclear lymphocytes (PMNs) (1,2,6). Bacterial lipases break down sebum triglycerides into glycerol, a growth factor for the bacteria, and free fatty acids that are comedo- genic and proinflammatory (1,6). The lipases and cytokines produced by the recruited PMNs each contribute to the breakdown of the follicular wall, eventually causing microcomedo rupture. The release of sebum, keratin, and free fatty acids induces an inflammatory foreign body reaction, resulting in the formation of inflammatory papules, pustules, and nodules (1,5,6). Therefore, by targeting the microcomedo, topical retinoids also help prevent the formation of inflammatory lesions that have the potential to heal with scarring. By preventing the formation of new microcomedones, topical retinoids produce acne remissions that can be suc- cessfully maintained for extended periods of time (2,7). These effects occur in what has be referred to as the “ideal state,” in which retinoids could be used in sufficient concentrations and frequencies to obtain the desired effect. Unfortunately, for many patients, the irritant side effects of these drugs—erythema, xerosis, burning, desquamation—can impede 100% adherence and improvement (2). Unlike oral reti- noids, the topical retinoids do not decrease production of sebum, but instead act by decreasing inflammation, normalizing keratinocyte differentiation, and increasing keratinocyte proliferation and migration (8,9).
Topical retinoids regulate gene transcription through an interaction with nuclear retinoid receptors. Nuclear retinoid receptors are ligand-dependent transcription factors that regulate the transcription of target genes in two ways (10). One mech- anism of action is via the direct binding to retinoid receptor cognate hormone response elements, direct repeats of six nucleotides, found in the promoter regions of retinoid-receptive genes (10,11). The second means of transcription modi- fication is the antagonism of nuclear transcription factors that bind to alternate response elements (AREs), thereby preventing the expression of genes regulated by these AREs (10,11). For instance, when a retinoid binds to the retinoic acid recep- tor (RAR) subtype complexed with the jun/fos transcription factors, it disrupts the interaction between jun/fos and the ARE, activator protein-1 (AP-1), and prevents transcription of AP-1 regulated genes (11). It is thought that this results in the anti- proliferative and anti-inflammatory effects seen with some of the retinoids (10 – 12).
Retinoid receptors, like thyroid hormone receptors, vitamin D receptors, and steroid receptors, are classified as nuclear receptors (12). There are two classes of nuclear retinoid receptors: RARs and retinoid X receptor (RXRs) (12). Each class of receptors consist of three subtypes: alpha, beta, and gamma, and in vivo, these
receptors exist as dimers (12,13). RXRs can dimerize with RAR, thyroid hormone receptors, and vitamin D receptors. RARs, however, can only dimerize with RXR (12). RAR alpha subunits are found ubiquitously, RAR gamma subunits are found predominantly in the skin, and RAR beta subtypes are inducible by retinoids only in certain tissues, including the skin (6,10). RAR and RXR subtypes bind as heterodimers along with the retinoid ligand to the cognate hormone response elements. Each retinoid holds a different affinity for each receptor subtype. The clinical response to each retinoid differs on the basis of the affinity for specific recep- tors, the expression pattern of receptor subtypes, and the cognate response element (10,11). Gamma receptor is the most important receptor involved in epidermal differentiation, and tretinoin has a high affinity for these receptors.
The first developed topical retinoid was retinoic acid, or tretinoin. Tretinoin’s flex- ible molecular structure allows it to bind all RAR and RXR subtypes, whereas tazar- otene and adapalene are more rigid, and therefore demonstrate receptor specificity (13). Tretinoin also has the capacity to bind cytosolic retinoid-activating binding proteins (CRABPs) that exist in two forms, I and II, and act as buffers for retinoic acid by controlling free intracellular concentration (3,10,11). Retinoid potency corre- lates with affinity for the RARs but not for CRABPs (11).
Tretinoin is available as 0.025%, 0.05%, and 0.1% creams, 0.01% and 0.025% gels, and 0.05% solution, with 0.025% cream having the least and 0.05% solution having the most irritation potential (2,3,6). Newer microencapsulated tretinoin gel and polyolprepolymer 2 gel forms are less irritating than other formulations of tretinoin (2,6,14). The tretinoin microsphere, available in 0.4% and 0.1% gel forms, encapsulates the molecule within a porous acrylate copolyer microsphere (2,15). This packaging system allows selective, time-released delivery of tretinoin to the follicle, leading to a decreased available concentration and lower irritation without diminishing the efficacy (2,15). In fact, the maximum comedolytic activity of tretinoin is reached at a concentration 5 to 10 times lower when the drug is used in a microsphere form (15). In addition, potential percutaneous penetration to the blood vessels is diminished (2,15).
Similarly, novel vehicles can allow controlled release of topical retinoids. Polyolprepolymer-2 is a material designed to help retain drug molecules in and on the skin when applied topically and has been shown to distribute tretinoin over time with equivalent efficacy to vehicle-free analogous formulations (16). The incorporation of tretinoin into this vehicle prevents rapid and excess percuta- neous absorption of tretinoin, decreasing irritation (16). In vitro absorption studies, guinea pig irritation models, human patch test studies, and acne clinical trials of tre- tinoin gel and cream containing polyolprepolymer-2 demonstrate that the absorp- tion of tretinoin during the first six hours of delivery is significantly less than that of standard preparations of tretinoin, but becomes similar after this time (16). Additionally, the total penetration of polyolprepolymer-impregnated tretinoin is less than vehicle-free tretinoin (16). Human patch tests demonstrated that both tre- tinoin gel and cream formulated with polyolprepolymer-2 resulted in less irritation when compared to their tretinoin gel and cream forms (16). Human double-blind clini- cal trials comparing tretinoin 0.025% gel and cream containing polyolprepolymer-2 to their commercially available equivalents demonstrated diminished xerosis, erythema, and peeling in the tretinoin polyolpolymer gel and cream formulations
(16). This decrease in irritation was achieved without compromising treatment effi- cacy (16). Although the exact mechanism for these actions is unknown, one pro- posed mechanism is that the degree of irritation from tretinoin is related to the rate of initial penetration of drug and while the efficacy is more a consequence of mean molecular flux (16).
The second topical retinoid developed for the treatment of acne is adapalene, a stable naphthoic acid derivative with both significant anti-inflammatory and comedolytic properties (6,11,17). Adapalene has been shown to have a more favor- able sideffect profile than either tazarotene or tretinoin (6,17). It has a specific affi- nity for RAR beta and gamma subtypes in the terminal differentiation zone of the epidermis and does not bind to CRABP I and II due to steric hindrance (3,6,11,13,18,19). Adapalene treats acne by causing epidermal and follicular epithelium hyperplasia, increased desquamation, keratinocyte differentiation, and loosening of corneocyte connections (11,14,18).
Adapalene is available as 0.1% cream, gel, solution, and pledget forms and is in clinical trials as a newer 0.3% gel formulation (2,20). The 0.1% gel has been shown to be as effective as tretinoin 0.025% gel with decreased irritation (2,20). The 0.3% gel has been shown to be safe and well tolerated for long-term use with almost doubled success over adapalene 0.1% gel without a significant increase in clinically relevant side effects (20). The release of adapalene from solution formulations such as lotions and hydroalcoholic gels is greater than when dispersed in creams or aqueous gels (18,21).
The anti-inflammatory effects of adapalene result from inhibition of the oxi- dative metabolism of arachidonic acid by the 5 and 15 lipoxygenase pathways and through the inhibition of PMN chemotactic and chemokinetic responses (3,11). As such, adapalene has demonstrated superiority when compared to reference anti- inflammatory agents such as indomethacin and betamethasone valerate (22). Other contributing factors for the lower skin irritation induced by adapalene include its different RAR subtype-binding pattern and more neutral molecular structure, which makes it less likely to nonspecifically interact with cell membrane function (3). Its high melting point and low solubility result in low flux through the skin, leading to high concentrations in the stratum corneum and hair follicle, where it can best act to prevent and treat acne (11).
Tazarotene is a topical retinoid that has demonstrated superior efficacy when compared with other topical retinoids in the treatment of acne (23). Tazarotene is
available in 0.05% and 0.1% cream and gel formulations (2). Tazarotene is selective for RAR beta and gamma subtypes (13). Although tazarotene does not directly bind to the RXRs, it does isomerize to 9-cis-RA, which weakly binds all RXRs leading to a degree of transactivation (21). The precise mechanism of action of tazarotene is unknown, however, it is postulated that through the activation of retinoid recep- tors, retinoid responsive genes are upregulated impacting the differentiation of keratinocytes. Similarly, by inhibiting proinflammatory transcription factors, tazarotene causes decreased cell proliferation and inflammation (21). Tazarotene penetrates the skin but accumulates in the upper dermis (24). The molecule remains concentrated here with very little absorption into blood vessels or lymphatics (24).
The topical retinoids induce specific changes in the structure and morphology of the skin. Normal epithelial cell differentiation is a vitamin A-dependent process (25). The presence of vitamin A alters the size of the keratin molecules synthesized by keratinocytes (25). When small keratin molecules are produced, a secretory-type
epithelium is generated. A stratified squamous epithelium is induced when larger keratin molecules are synthesized (25). In the absence of vitamin A, cells differen- tiate toward keratinizing epithelium (25).
Keratinocytes within each layer of epidermis possess a distinct set of proteins unique to their stage of differentiation (26). As undifferentiated basal cells mature and migrate up through the epidermis, their pattern of protein expression changes (26). Once these cells arrive at the stratum corneum, the intracellular organelles have been catabolized and cytoplasmic and membrane proteins altered so as to produce a layer of dead corneocytes with thick keratin fibrils within a dense matrix (26). As a group, the retinoids alter this process by inducing dose-specific ker- atinocyte proliferation and reversing the abnormal keratinocyte desquamation found in acne (26). This helps form a thicker layer of suprabasal cells, but a thinned, loose stratum corneum (2,3,26). Topical retinoids increase the rate of kerati- nocyte turnover resulting in an increased rate of follicular proliferation and differen- tiation (24). This results in decreased follicular occlusion and faster microcomedone clearance (3,24). Specifically, topical retinoids cause basal and spinous epithelial cell proliferation and reduce the size and adhesion of corneocytes by decreasing filaggrin expression and suppressing the normal proteolysis of keratins 1 and 14 (1). In addition, retinoids thin the stratum corneum by causing desmosomal shedding, decreasing tonofilaments, and increasing keratinocyte autolysis (1,8,27).
Epidermal cell commitment to proliferation and differentiation can be altered by the topical retinoids. Normal keratinocyte differentiation involves the expression of keratins K1 and K10 (26). An alternative pathway of differentiation compatible with hyperproliferation occurs upon suprabasal expression of K6, K16, and K17 (26). Cells expressing K6 and K16 enlarge as they migrate to the surface and do not produce keratohyalin granules or lose their nuclei before desquamating (26).
The dose-dependent epidermal acanthosis results from increased number of cell layers, not from hypertrophy of individual cells (9). There is no change in structure or size of sebaceous glands after treatment with topical retinoids (9). All of the above factors demonstrate that comedolysis is retinoid-specific, not simply secondary to desquamation (3).
Retinoids also have secondary effects that facilitate acne clearance. By weak- ening and loosening the cornified layer and decreasing the number of corneocytes, skin permeability is increased (2). This facilitates the absorption of other topical agents, such as antimicrobials or benzoyl peroxide (2). Increased cell turnover
within the follicular epithelium also allows more oral antibiotic to enter the follicu- lar canal where P. acnes is concentrated (2). This increases antimicrobial activity, lowering the potential for antibiotic resistance from inadequate concentrations (2). By increasing the rate of acne clearance, the overall duration of antibiotic treat- ment and chance for antibiotic resistance can be reduced (2,6). In addition, this modification of skin morphology creates a more aerobic environment and decreases the ability of P. acnes to proliferate (2).
USE AND SIDE EFFECTS
Proper selection and usage of the topical retinoids is crucial to maximize efficacy and patient adherence and satisfaction. Treatment should begin with the lowest concentration of medication, usually in a cream-based form if available (21). Appli- cation should occur at night to dry skin, 20 to 30 minutes after the face has been washed with a mild, nonsoap cleanser (21). A pea-sized amount should be
dispensed and equally divided over two index fingers, which then dab the medi- cation evenly onto opposite sides of the face and spread the medication into a thin layer until no visible product remains (21). Hands should be washed after- wards to avoid retinoid dermatitis (21). Application should first occur every other night for one to two weeks depending on the skin type so as to minimize the initial irritation that may otherwise discourage adherence to the treatment regimen (1,21). Oily skin is better able to tolerate the potential irritating effects of the retinoids and, as such, a shorter introductory period may be utilized (21). Non-comedogenic moisturizers can be used to minimize xerosis, erythema, and stinging (2). Patients should be instructed that as long as four to six weeks of use may be required before the onset of efficacy and that an initial flare in acne may occur following two to four weeks of use due to an accelerated evolution of pre- existing microcomedones (3). Periodic encouragement and reassurance may be necessary. Four to six weeks of nightly application should occur, after which the concentration may be increased if the desired results are not obtained (21). An additional benefit to topical retinoid use is the potential to improve and prevent the postinflammatory hyperpigmentation often seen in darker skin types as acne lesions heal.
MINIMIZING SIDE EFFECTS
Side effects of topical retinoid use include initial local irritation, including erythema, burning, stinging, peeling, and xerosis (1). These symptoms usually peak after two weeks of use, and subsequently diminish and then resolve once the skin adapts to the use of the product (1,3,18). Factors influencing the extent and duration of irritation include concentration of the medication used, vehicle of delivery, frequency and amount of application, skin type, and environmental factors such as use of abrasive cleansers or other topical alcoholic agents, ambient xerosis, and exposure to the sun (1,6,14,18,28). Higher concentratations or use of a gel or solution vehicle predisposes to the most irritation. Topical retinoids produce more irritation when used by patients with eczema, rosacea, or other conditions of skin sensitivity, including exposure to extreme weather (2,14). In these patients and during the winter, lower concentrations and the milder forms and vehicles should be utilized (2,28). Individual patient variation does, however, occur and some patients may actually tolerate gels better than creams, perhaps because they are more difficult to apply. Adapalene and tretinoin are photoirritants, not photosensitizers, meaning that there is an increased susceptibility to irritation upon sun exposure, and therefore minimizing sun exposure through sun avoidance and the use of sunscreen or physical blockers is imperative (14,28).
For patients who are unable to tolerate even the gradual introduction of the mildest topical retinoids, short contact therapy can be utilized. Short contact therapy is a safe and effective method that involves applying the topical agent for a brief period and then washing it off (13). Patients should initially leave the reti- noid on the skin for two minutes each day, increasing by one minute at least every three days as tolerated and without causing adverse effects (13). If irritation occurs, time of exposure should be decreased by 30 seconds for at least three days and then incremental increases can be resumed (13). Studies have demonstrated somewhat diminished efficacy than overnight tazarotene, but overall good results without irri- tation in patients who otherwise would be unable to benefit from topical retinoid therapy (13).
The type of vehicle used to deliver the retinoid influences the degree of skin penetration, the clinical effect, and the side effect profile, including the degree of photoirritance (1,6). Future formulations suspending topical retinoids in a foam vehicle could potentially create a nongreasy, no-residue, less-drying formulation to more effectively deliver the medication over hair-bearing sites such as the back and chest (29).
Acne vulgaris is an almost ubiquitous condition. When antimicrobials are used alone, there is a risk of creating widespread, multidrug resistance of P. acnes as well as other skin flora such as Staphylococcus aureus (2,5,30). This potential resist- ance can be limited by combining agents that act on different steps in the mechan- ism of acne pathogenesis. When topical retinoids are used in combination with oral or topical antimicrobials, excessive ductal cornification, P. acnes proliferation, and inflammation can be simultaneously targeted for increased efficacy, faster onset of effects, decreased total antibiotic use and risk of resistance, and shorter overall duration of treatment (2). The combination tretinoin with topical or oral antibiotics has been shown to be superior to either alone in decreasing lesion count, increasing rate of improvement, and decreasing levels of P. acnes and free fatty acids (8,14). Similarly, the combination of adapalene with topical doxycycline or clindamycin shows increased efficacy in improving total, inflammatory, and noninflammatory lesions including a faster onset of action without an augmentation in side effects (17). In addition, combination use of adapalene offers an anti-inflammatory benefit, which minimizes the increased risk of irritation that occurs upon increasing the number of topical treatments (17).
Similar results were found upon combining retinoic acid and antibiotics, with a reduction in the initial retinoid-induced flare of lesions through the antibiotic use (3). When combined with a benzoyl peroxide oxidizing wash—which demonstrates an effective bacteriostatic concentration after only 20 seconds of use—tretinoin 0.1% micro gel decreased P. acnes counts without increasing irritation (6,31).
With long-term use, however, overall improvement is similar with combi- nation therapy as compared with topical retinoid use alone (14,23,32). Increased reductions in open and closed comedones, papules, and pustules were demon- strated when tazarotene or tretinoin creams were combined with clindamycin/ benzoyl peroxide as compared to either retinoid alone (14,32).
Finally, it has been shown that combining topical retinoid therapy with oral antibiotics for inflammatory acne is more cost-effective than using an oral retinoid alone when accounting for pretreatment and treatment laboratory tests, pregnancy tests, and diagnostic fetal tests after a potential unintended pregnancy (33).
A new combination clindamycin 1%/tretinoin 0.025% gel, Velac, has demon- strated greater and faster treatment success in initial clinical trials when compared to clindaymycin or tretinoin gel alone and provides a convenient means of appli- cation, which may improve patient adherence (12). The side effect profile of Velac was similar to that of tretinoin gel alone, with only slightly higher irritancy than clindamycin gel alone (12).
And as previously discussed, the use of topical retinoid in combination with oral antibiotics can decrease time of use of antibiotics, decreasing risk of resistance, adverse response, or drug interaction.
SYSTEMIC ABSORPTION AND TERATOGENICITY
The teratogenic effects of oral retinoid therapy are well-documented. Tretinoin penetrates the skin and accumulates in the upper dermis with very little absorption into blood vessels or lymphatics (24). Several studies have evaluated the systemic effects of topical retinoid therapy. Tretinoin 0.1% to 0.2% applied for extended periods demonstrates minimal to no increase in tretinoin levels above endogenous and these level changes have not been associated with teratogenicity (1,21). Worobec et al. (34) studied the percutaneous absorption of 0.05% tretinoin by using radioactive labeling and measuring the levels of retinoid found in the urine, stool, and plasma, after repeated applications. An absorption level of 1.38% to 2.13% was found, correlating to an insignificant increase in the endogenous level of tretinoin and a very low risk of systemic toxicity (34). When 0.1% tretinoin cream, 0.1% Tazarotene gel, and 0.1% adapalene gel were applied over 26 days, the respective mean maximal plasma levels of were 4.7, 0.14, 0.04 ng/mL, which are all well below the mean endogenous level of 6.6 ng/mL of all-trans-, 13-cis- þ 13-cis-4- oxo-RA (21). Other studies have also found that overnight tazarotene use produces levels of tazarotene and tazarotenic acid levels lower than endogenous, with the highest rate of absorption shown to occur after tazarotene was applied under occlu- sion for 10 hours resulting in ,6% absorption of total applied dose (13). In fact, diurnal and nutritional factors alter endogenous plasma levels of retinoids more than widespread topical use of all-trans-RA (35). Buchan et al. (35) evaluated the daily use of radiolabeled 0.025% all-trans-RA over the face, shoulder, and upper chest and demonstrated a percutaneous absorption in the range of 0.1% to 7.2%, considered to be an insignificant increase in endogenous levels. Daily ingestion of the 50,000 IU of vitamin A, however, tripled the endogenous level of all-trans-RA, doubled the level of 4-oxo-13-cis-RA, and increased 13-cis-RA six times (35). The recommended daily allowance of vitamin A for male adults is 900 mg/day and fornonpregnant, nonlactating women 700 mg/day of vitamin A, with the recommended dosage actually increasing to 770 mg/day in preganancy and to 1300 mg/day in lactation (36). On the basis of this information, it is very unlikely that topical retinoid use could cause systemic toxicity.
Although there is a lack of studies on humans, topical retinoids have not demonstrated teratogenic effects in animals (24,37,38). Nevertheless, tretinoin should be used cautiously in pregnancy and lactation while tazarotene is contraindicated.
Topical retinoid therapy is a safe, effective, economical means of treating all but the most severe cases of acne vulgaris. The retinoids serve as the cornerstone of treat- ment and should be the initial therapeutic step, either alone or in combination with topical or oral antibiotic therapy and benzoyl peroxides. Once a patient has achieved adequate results, the topical retinoid should be continued alone as main- tenance therapy to maintain lesion remission (2,20,33).